Good morning and welcome everyone. Thanks for being here in New York City with us, in the webcast. It's a real honor and a privilege to have all of you here for our second Analyst Day, our epilepsy day, today. As you can guess, we're gonna be making some forward-looking statements. I'm not gonna be reading all the text here, but I do encourage every and each one of you to look into our SEC filings, especially our Form 10-K, filed with EDGAR. Why are we here today, right? We're gonna be talking mostly about the epilepsy franchise. It would be disingenuous not to talk about the other two franchise, like each one of them have significant value creation for patients.
First and foremost, it should start and end with who you are serving as a company, as a community, as investors. The second is there's a number of real big events for Praxis coming up. That was the disingenuous part. I'm just not addressing that upfront. I'm incredibly excited and all the team at Praxis and everyone there in the community, and we know healthcare professionals are as well, with PRAX-944-221 Part B, the randomized withdrawal phase for our essential tremor study reading out. I guess now I can say in a few weeks since May is right on the over the weekends. It's starting at least. We're not gonna release data over the weekend, so we're clear.
Right after that, our psychiatry franchise having one of the biggest readouts, I would say, in the year in biotech, in our view at least, that is Aria. We're so incredibly excited there because, as I'm sure it touched the life of many of you, it definitely did in my family, the psychiatry in general, those conditions and depression most specifically, has such a huge unmet need. We're really looking forward to that. Now, if you were to talk about unmet needs, you can go across the board here and all the diseases we're gonna be discussing today, and there is not even a way to classify, right? A patient, a family, a system of supports, the physicians, the nurses that are around those patients, there's always the unmet need.
I think it's once again a little bit disingenuous to talk about higher or lower. We're gonna be talking about the needs of individuals here and their support networks and the people that struggle, to be perfectly honest, on helping them every single day. That's the general direction what you're gonna hear. I wanted to bring back to how do you connect all of this, right? Hopefully today is gonna be more clear than ever been, for Praxis at least. On what we see this connection between the different nodes, transmitters, networks, cellular process, disease processes on those three franchise has been fundamental to how we thought about the company, but it's more fundamental about how we develop, how we reduce to practice everything we are doing every single day, moving forward.
Now, the underpinning of our very first thoughts when we're looking for a program, for a drug, for how to address this, what is the most unequivocal item that we can look into and say, that thing, whatever the thing is, does generate a pathological process that I understand with a one-to-one relationship or a one to multiple relationship. In our view, is anchoring the entire pipeline in genetics. The aha moment here is that when you study genetics of epilepsy, for many of these studies being done before, Dr. Petrou is gonna be going through some of them and the inspirations there. Originally, we're thinking that's gonna be it, right? We're gonna look into some of these genes, and they're gonna be fairly exclusive, but they are not, as we all know. That allow us to really ask, how can we modulate the processes?
How can you modulate the networks? How can you really help more patients outside of that? We chose very deliberately to go into movement disorders and into psychiatry on top of epilepsy. There could be many other here. There's a number of prioritization choice that I want to make before we continue to move here. So the first one, I would say we all know biotech is a beautiful market right now, right? Everyone is incredibly happy with the performance of the sector. But what comes with it, the positive that comes with it is discipline and focus are even more important. Focus and discipline on the science, as I am absolutely convinced that at the end of the day, you're gonna see how much we have.
Financial discipline in terms of who, the kind of individuals that we want in the companies, how we distribute work inside and outside, but really the day-to-day expense management, and so on. With part of that, one of the things we did decide to do is to discontinue our program in senterinassant and TN-4562. There was nothing wrong there on the safety. There was nothing wrong there with how the program was going. It did not meet two of the key criteria for us. I wanted to say that right before I move to the next concepts that has been true to how we filter these drugs. First and foremost, as I just said, every single program is anchored in genetics. It starts and ends right there, right?
If you do not understand the genetic process, and it's not to say that if others do a different way, it's wrong. There is no right or wrong. There is just the right is the drug that gets to the patient. How we get there are many different ways to do so, but that is a filter for us. That is a principle, right? From there, we chose and we are committed to two principles. One is translational tools that are real. What that mean is we expect something to change. We measure that thing, let's say electrophysiology, quantitative EEG, a fluid biomarker, whatever it is, and it does change, and we can replicate that in humans, and that the drug's in the brain.
I think if you look into the most recent issues that happen in CNS, since CNS gets this bad rep for higher risk, they're mostly because that step was not properly fulfilled. If you can jump straight into a later stage without understanding if proper concentrations of the drug's in the brain and if it's doing what is expected, I would say, of course, something's gonna happen that is not desirable. We don't ever go over that step. The one I was referring to is the one to the other side of the slide here is if we cannot generate proof of concepts quickly and effectively, our filter for progress puts a stop on it, and that's what happened with suntenazon and TN. That has nothing to do with anything else.
What gives us on the other end is capital to make sure we continue to run the company, number one, from my perspective, from Tim Kelly's perspective, that I'm sure you would appreciate. Reinvest as well as needed on the high potential programs that we have. To finish with the circle here, what I would say is we talked about patients again. It's an incredible cliché in the industry, right? I don't believe there is any single company out there that say they are not patient-centric. I'm not gonna go into this, things on the wall or things on The Wall Street Journal saying how patient-centric we are. We are, and you can see this every single day on the questions we ask, on the unmet needs we meet, on the ability to actually directly ask the tough questions.
Should we develop a drug here? There is really a need. Can we be best or first or first in class and drive the benefits to the patients? You're gonna see throughout the day that that's exactly what we are doing. Now, none of those principles matter if you don't get at the ends and generate sufficient cash revenue, free cash flow, hopefully one day, to reinvest and to continue to help because it's to do this again and again that it says in our mission. All right? If you go back to today and to the markets in epilepsy, there are two major areas we're focusing on. The first one is common epilepsies, and you're gonna hear this from Bernard, you're gonna hear that from our experts that are gonna be speaking today, and you're gonna hear a little bit from Steve as well.
It's how to address the significant number of patients in the market right now that are just struggling with residual seizures or equally worse or equally bad with many other things that happen in their life because we have this single focus oftentimes on reduction of the seizures or seizure freedom, but that is a surrogate to everything else that happens on their life. From a purely size of the market perspective, we're talking about a very significant multi-billion dollar opportunity for us, and very concentrated as well. One of the things that the epilepsy community did really well was, one, form the medical schools, the programs, really good neurologists that are dedicated to these patients, and that helps a lot when we're getting in a given markets.
The second is really understanding why what's happening and the choices they have, as we're gonna hear. That's one side of the equation. The other sides of the equation is the rare or more defined epilepsies. While there are many, as Steve is gonna talk a little bit about that, we always go through two major filters. Just to say that again. One is business. If there is no way to actually get this drug to the markets and to reinvest that in another drug, it's probably a fool's errand to go into that direction. It's not the markets to be, it's the markets today, meaning the number of patients we understand right now are in needs. Every single program we start, we ask, are those patients actually seizing, having other comorbidities?
You're gonna hear about some really cool initiatives we're having to get that upfront. But even if you put all of that aside and you get exclusively the indications we're gonna be talking today, we're talking about a much bigger market from a purely revenue perspective than anyone else has right now in development for epilepsies. Our press release that was issued about 10 minutes ago says in the headline that we have the largest pipeline in epilepsies in the world. That's very true in terms of not only addressing the patients, the collection of it, how we go about the science modalities, quite importantly as well, in general, from a revenue potential perspective. How does it fit with the overall pipeline, right? Once again, as you're gonna hear throughout the day here, the next few hours, epilepsy serves as two purposes.
One, standalone therapeutic area. Hopefully I'm not gonna have to re-convince anyone that is a very potentially profitable one. The second is a gateway or a springboard to many other diseases in the brain. Some of them we might develop ourselves, others there might be better companies to do it. We're more than open to have conversations, partnerships, and so on to continue to advance in creating value to all these patients out there and shareholders alike. Now, you're not gonna be hearing from me for much longer here, so I just wanted to take a moment to first introduce and thank two of the world experts in epilepsy that are joining us here today. Dr. French is gonna be talking a lot about really the, I'll say, conundrum, as you're gonna see, about treating these patients.
You can read the bio here, but I think it goes without saying, provoking us, we should do better. That is, the bar is too low right now. I'm sure, Dr. French, that's a little bit what we're gonna hear from you. Thank you so much for being here. Dr. Friedman is gonna walk us through a little bit what is the life of a physician in a given day treating a patient. First time that we talk about it, and I saw his talk was quite moving because we think cohorts in drug developments, right? Every time we're looking to this, we're like, "Okay, how many patients? What is the cohort? What is the average?
What is the general distribution of a given issue? When a physician is treating a patient, they're looking into the patient's eyes or their parent's eyes and saying, "That's what I can do for yourself, for your kids, for your parents," and so on. That's quite powerful as well to understand. In today's agenda, after this, boring introduction by myself, we're gonna get to the actual meat, of it, right? Professor French is gonna talk a little bit about what we just discussed, like what is the unmet need right now, in epilepsy, management. Not the unmet needs superficially, but what is really going on? What can we do for these patients? I'm sure you're gonna find it, incredibly enlightening. Then, Dr.
Petrou, our chief scientific officer, are gonna talk about what we do in two aspects as a company. The very first one is how do you think about a system? From a system perspective, how do you get these things together? What is the secrets that we have here? To be honest, some of them are protected by patents and so on, so it's a little bit of a secret as well. You're gonna hear from Steve, someone I absolutely adore working with every day and a person who does not sleep because he joins every single meeting that we have from Australia, which I very much appreciate, Steve, from you.
Once we talk about the tools we use, Steve's gonna say, "Okay, how did we do it?" There's a lot of cool things that we're gonna be hearing that we've been doing. It's been a little bit on the back burner from the public side, but not from the internal sides. Dr. Friedman's gonna come after and go through this case and the idea of why do we need other drugs, why those drugs, and hopefully we're gonna be helping. Hope's not a strategy. I always say that, so a lot of people here are gonna be like, with the Praxians at least, they're gonna say, "Really, Marcio? Hope? It's not hope.
“What is the strategy we have to actually drive this?” Bernard’s gonna come at the end and talk about our three epilepsy programs gonna be in the clinic by the end of the year. Now, we’re not into bragging as a company. We believe delivery is better than bragging. Nicole has been reminding me and Bernard that we should be talking a little bit more about what we did in the last 12 months. We did clear six INDs with the FDA during the last 12 months. We think that is just what companies should do, and that’s why we’ve not been talking about them every single day. I’m gonna be forever indebted to the team at Praxis for working so hard, so diligently, so close to the agency.
Instead of complaining on the public calls, driving to get those things delivered. Just want to say a big thanks to the team, 'cause obviously we're here today, but we're supported by 150 other Praxians out there. Much more to come. Many more registrations, trials. Obviously incredibly excited to be kind of here-ish, virtually again in a couple weeks to talk about PRAX-944 , in several weeks to talk about PRAX-114 , and then to continue to build the company. Without further ado, Dr. French.
Thank you. It's a pleasure to be here and also to see how many people are interested in epilepsy. It makes my heart feel good. I'm gonna talk a little bit about unmet need in epilepsy management. Here are my disclosures. I work for something called the Epilepsy Study Consortium, which is a nonprofit, and I am happy to work with many companies that are developing drugs in this space, including Praxis. By a conservative estimate, you saw some of these statistics already. 50 million people worldwide have epilepsy, and the annual incidence ranges from 20-73 cases per 100,000. One in 26 is the number we use at the Epilepsy Foundation, where I'm also the chief medical officer. 5% of the people in this room have or will have a seizure in their lifetime.
The most common incidence is in childhood, then a little bit of a plateau in the middle years, and then a sharp increase, as we now understand, over the age of 60. You guys, your risk isn't over yet. About 30% of patients have an identifiable neurologic disorder, genetic underlying predisposition or whatever, and the rest, actually, we don't know why they have epilepsy. We make a diagnosis in a number of different ways based on what type of seizures they have, the clinical context in which they occur, the EEG which they present with. We have been very fortunate to have many, many new anti-seizure medicines in the pipeline. I have added the most recent one on this slide, very up to date.
Ganaxolone in the last couple of weeks was the first drug to be approved for CDKL5 deficiency disorder. Despite our success in getting many, many drugs out there, some might say we haven't made the progress that we may be expected to make. Probably 30 years ago, this initiative was started by Professor Brodie, who many of you may have heard of in Glasgow, who has a first seizure clinic. He sort of established the numbers that we all use now, which is that if you gave somebody an anti-seizure medicine, and it didn't seem to matter really which one it was, about 50% of the people with newly diagnosed epilepsy would have their seizures come under control, and they could expect a very nice life as long as they continued to take their medication.
If they failed that first drug, they still had an opportunity to improve with a second drug, but that only added about 13% additional seizure-free people. Many of those people were people who had failed drug number one, not because they continued to have seizures, but because they had a side effect that they couldn't tolerate. Once people had failed two anti-seizure medicines, the likelihood if you went to a third monotherapy, a fourth monotherapy, polytherapy or whatever you wanted to do, there was very little additional benefit after that. In fact, I was on a commission many years ago that established the definition of treatment-resistant epilepsy as failure of two adequately used anti-seizure medicines to control seizures.
Studies in the 1980s, as I said, established that critical ratio of treatment of 60%-70% response to anti-seizure medicines and 30%-40% treatment-resistant. We all expected with, you know, all these wonderful new drugs coming forward that there would be a change in that ratio. The data does not support that. Kwan and Brodie went back to their clinic. It's actually now a decade ago, but in 2012, the majority of the drugs that you saw on my slide were already available to these people by that time. Yet the number that were seizure-free had only risen from 64% to 68%, which is rather disappointing.
That leaves us in the position that we are in now, where we have treatment for 2/3 of patients, and we can pretty much give them a variety of drugs. None of the drugs are perfect, but we can give them a variety of drugs, and they will become seizure-free. What do we need? That's what we're here to talk about today. We need treatment for that 1/3 of people who have not gained control from the other anti-seizure medicines that are currently available. We desperately need treatment for difficult pediatric syndromes and the rare epilepsies, those 35,000 individuals that we were talking about. Because, you know, even the small gain that we've made in the common epilepsies, we have not made in the rare epilepsies, and essentially almost all of them continue to have seizures.
Many of those, as you know now, are identified as monogenic epilepsies, and more and more over time are being identified. We would love to be able to predict, and I've spent a lot of my own research time looking at, can we take somebody who first shows up in the clinic and predict that somebody's gonna do well or somebody's not gonna do well, so that we can move on to more aggressive therapy earlier. We need improved options for newly diagnosed patients because even though we can get them seizure-free 2/3 of the time, they unfortunately have to tolerate a lot of chronic adverse events in order to do that. I would love to have more medications where people can take them and not have an impact on their quality of life.
We need drugs that attend to people's comorbidities in the common epilepsies and in the rare epilepsies. In the common epilepsies, depression, cognitive slowing, memory impairment are often coming along for the ride. In the rare epilepsies, depending on the monogenic epilepsy, there is a host of comorbidities that we know of, whether they be cognitive or psychiatric or movement as we heard. Of course, finally, we would love to have drugs that don't only work on seizures but work on the underlying disease. Just a moment to say that, you know, even though we get t2/3 of people seizure-free, they are also burdened because we are not treating the disease by having to take that medication on a daily basis, some of them for the rest of their lives. I and Dr.
Friedman can give you many examples from the clinic of people who had perfect adherence for years and years and years, and then missed a single pill and had a seizure. You know, that kind of burden is one that I think is hard for all of us to even fathom, that missing a single pill could have dire consequences on your life. We seem to have no trouble finding drugs with novel mechanisms, and, you know, even recently, for example, more potassium channel openers, lots of GABA PAMs, mGluR2 PAMs, and so on and so on. Will those drugs translate into better treatment, better efficacy?
Interestingly enough, to date, it almost seems like the opposite, that we understand the drugs that have mechanisms that treat epilepsy well symptomatically, and we find that many of these novel mechanisms have not translated into better efficacy or better tolerability. You have heard me use the term anti-seizure medicine many times already this morning, rather than what you probably all understand to be the term, which is antiepileptic drug. The International League Against Epilepsy, which is our naming body, is actually in the process of officially changing the name, so get used to it, to anti-seizure medicine. The reason is because we feel it's extremely important to signal to everyone, to people who are developing new therapies, to patients, to our community, that the medicines that we are currently giving are symptomatic treatments.
You know, I use as my example this little guy here. All along here, we have been treating. If he had pneumonia, it's like we're treating his cough, and we may make him feel better, or we give him an antipyretic for his fever, but we're doing nothing for his underlying pneumonia. Obviously, we would like to not only treat the symptom, we would like to treat the disease. We would like to get mechanistic. We would like to get disease-modifying. We certainly hope that we are on the cusp of having treatments from all the pharmaceutical companies that will provide us this benefit.
We're sitting here at the dawn of some of these new therapies saying, "Can we predict which drug is going to be better, which drug is actually going to help our community, is going to advance us?" You know, everybody who was on that list that I showed to begin with certainly thought that they had a drug that was going to move the needle. It turned out not so much. How could a drug differentiate that's gonna help us in the clinic, that's gonna help with the patients that Dr. Friedman is gonna tell you about? Well, a drug could differentiate in a number of ways that would be important to us. The first one I've already discussed, which is it could be disease-modifying. It could be targeted to a specific population.
You know, now we're sort of shooting darts in the dark and hoping that it hits. If we knew that a certain drug was better for a certain population, that would really help us because many of these patients, once they are treatment-resistant, have to go through 10 or 15 drugs, and eventually they may indeed find one that benefits them, but the odyssey to get there is pretty terrible. We could have a drug that has a clear and indisputable advance in treating resistant epilepsy. I will give a shout-out to cenobamate because of the recent drugs that have been approved. That one certainly did get more patients seizure-free than we've seen in for past drugs, and we need more of that and better of that. Seizure freedom. That's what we're looking for. That's what our population is looking for.
We need drugs that are better tolerated. You know, we don't want to. You know, I tell companies when I talk to them, "Don't presume that just because somebody has treatment-resistant epilepsy, that they're willing to tolerate more side effects to get seizure control." They still have to live their lives, you know. If you were them, you wouldn't wanna, like, sleep 15 hours a day in order to have seizure control, and neither do they. Less issues for women of childbearing potential because we have very few drugs that are safe for, you know, the developing child, as well as safe for the woman who's taking it during pregnancy. Specific efficacy in difficult syndromes such as Dravet and Lennox-Gastaut.
If we had one that was longer acting so that adherence would not be as much of an issue, that would be a blessing as well. Seizure freedom is what our patients are striving for. In add-on studies, until cenobamate recently, usually less than 5% of subjects were able to obtain seizure freedom even for the three months of the treatment period after we randomized them to drug or placebo. There is great opportunity to develop new therapies that increase the rate of seizure freedom or even get people to 75%-90% seizure reduction. This number was created a long time ago of you know what constitutes a benefit.
50% reduction in seizures constitutes a clinical benefit, and maybe that's true, but I can tell you that our patients certainly are not satisfied when they get 50% reduction. You know, if you're having seven seizures a month and you go down to 3.5 seizures a month, you still don't know when you're gonna have a seizure. You still can't drive. You still, you know, potentially can't go out in public. You still might injure yourself, et cetera. You still might die of sudden unexplained death. As I said, it all comes down to risk versus benefit. Don't forget that the balance of adverse effects and risk of harm to benefit is important even to individuals with treatment-resistant epilepsy.
There is something else about adverse effects that I want to emphasize that's really important, and that is that most of our drugs that have known mechanisms now, such as sodium channel blockade and GABA increase, et cetera, have a clear dose-response relationship in clinical trials. The more people get, the better off they do. But unfortunately, if you look at this graph, what you're looking at is sort of a theoretical construct of the percent of people who might achieve seizure freedom with a drug, and the dose that they can tolerate. They can only get benefit up until the point where the side effects become intolerable. I remember, you know, vividly a guy who was in one of my clinical trials with a drug that's already on the market, and he was having a seizure every single day.
In the randomized controlled trial, he became seizure-free. I was thrilled. As his investigator, I was completely thrilled until he came to me and said, "I'm dropping out." I said, "How can you drop out? You went from a seizure a day to seizure-free." He said, "I can't stay awake at work. I'm gonna lose my job. I go to my desk, and I fall asleep at my desk. I cannot have that, and I can't stay on this drug." There is a toxicity limit to how much people can take. Imagine if you could take that same mechanism. Whoops. That didn't work. Can we go back? Yes. No. It's not. The animation isn't working, and it's such a good animation. We'll tell you about the animation.
If you could move that toxicity block over, you could actually uncover more efficacy. You could get more people seizure-free. The example that I just gave you was the critical example. You could get more people seizure-free. You don't only get the benefit of improved tolerability if you can reduce the side effect burden of a mechanism, but you also potentially get the advantage of more seizure freedom. We've seen that, for example, in sustained release formulations. Same drug, but just you don't have a peak dose toxicity. You can give people higher exposure over the course of the day, and more people will be seizure-free and happy. Let me just change gears, shift gears for a little bit and talk about precision therapy. Recent studies of emerging anti-seizure drugs have targeted the rare epilepsies.
Dravet syndrome has been targeted by fenfluramine and cannabidiol. Lennox-Gastaut, clobazam, rufinamide, cannabidiol, and fenfluramine. The question is, we're talking about the benefit of precision medicine. Is this precision medicine? Up until this time, the studies have determined that if you take this drug and you give it to this specific population, it works better than placebo. However, if you had taken that same drug and given it to a different population, would it have worked better? Would it have worked worse? We have no idea. Or if you took a different drug and you gave it to that population, maybe even one that's already on the market, would it have worked equally as well? Our precision therapies to date, you know, I worry about pseudo specificity.
Meaning, you know, if I gave a drug to blue-eyed people with depression and it worked, I could claim that my drug was beneficial for blue-eyed people with depression. That doesn't mean it doesn't work on brown-eyed people, nor does it mean it's a better drug for blue-eyed people than some other drug. It sure gives the impression it does because I tested it on blue-eyed people with depression. These studies have not proven either that the drug is more effective than other potential therapies or that the drug will be more effective for this syndrome than any other syndrome that could be tested. We need better precision in our precision therapy. We hope that we're getting there, right? We want precision therapy with disease modification. We want targeted drugs that actually target to the pathway that we already understand is present in those patients.
That's the hope for the future, to correct pathology caused by a specific mutation or mutations. You know, we got a little hint of that maybe with everolimus for tuberous sclerosis, because in tuberous sclerosis, we know what the mechanism is, which is an mTORopathy. Everolimus normalizes the mTOR pathway and also is disease modifying for some of the other problems that happen in mTORopathy. You're not only targeting the seizures, you're targeting other comorbidities, and that's where we wanna get to, right? Targeted gene therapies is also a hope for the future. One hope that's already in the clinic and trials is antisense oligonucleotides with haploinsufficiency disorders, with one bad gene and one good gene, where you're stoking up the protein of increasing the amount of protein that's missing because of the bad gene that can't produce it.
Do epilepsy patients represent a satisfied market? I do not believe they do. There are many issues with existing anti-seizure medicines. One-third of them continue to have seizures. One-third, by estimation, have dose-related side effects. There are no disease-modifying therapies yet. And we are hoping that in the future, we can really address many of these problems, and hopefully we'll be hearing something exciting for the rest of the day. Thank you very much for your attention.
I'll serve as MC just quickly. Just wanted to invite Steve to come here, and as a lot of you know, he's gonna do a little introduction. Steve's being a co-founder of the company. A lot of the ideas from the very beginning come from his lifelong dedication to CNS. He's gonna go through a little bit on how we do it, why we do it, and why we are so excited here at Praxis.
Thanks, Marcio, for that. As Marcio said, I'll just give a if you indulge me for 30 seconds, a bit of a background on how I ended up here. I was a career academic. I've been dedicated to really neurobiology of disease for the past 25 years of my academic career. Up until about a week ago, I was the director of the Florey Institute of Neuroscience and Mental Health. It was Australia's largest neuroscience institute, about 700 staff members, quite a large operation with a broad focus on neurodegeneration, epilepsy and basic biology. I've been involved with Praxis, as Marcio said, since about 2015 when it founded. It was founded really on the cusp of an amazing advance that we saw in the genetics of rare disease, as Dr.
French was mentioning. At that time, we really for the first time understood the genetics of these sporadic cases. That presented an amazing opportunity to really do something about it and use that knowledge. That's been a really big part of my career, is how do we take the learnings from clinicians, from basic scientists and actually turn it into impact. I've been very passionate about that. I've worked with parent groups. Some amazing parents I've worked with over the years. I've worked with to found Praxis and I've found it almost irresistible to not get more and more involved.
For the past two or three years, I've been working, you know, my day job for 10 hours and then putting another 10 hours in in the evening, sleeping about three or four hours a day. I've made the commitment, and Marcio set up, I think, such an amazing leadership team and an amazing team within Praxis, but it's just too compelling. I'm leaving my job as director. I'll have a small footprint to keep the lab going and some projects that are collaborating with Praxis, but I will be doing 95% of my time as chief scientific officer, and I'm just so excited about the future of that. So excited where the field of genetics and where the clinicians and the research have taken us to this point.
I wanna share in a little bit of that excitement today. That's enough about me. Let me talk a little bit about why we're here today. This is a great question: Why epilepsy and why now? I think whenever you answer questions like that, it's always good to know where you come from. I won't do a long history lesson 'cause that's not what we wanna do today. This is where it all started. Why we are talking about and why Praxis exists, why we're talking about making medicines, why we're informed by genetics comes from the studies of a noted American epileptologist called William Lennox. He was studying twins. He's asking the question, "Is there a genetic element?" You study identical twins, or you study non-identical twins.
What he found, unequivocally what he found, if there was epilepsy in an identical twin, the chances of epilepsy occurring in the other twin was very, very high. Way higher than in non-identical twins. This is just one example of many of two lovely girls from the forties, Caroline and Eleanor, 16, 17 years of age. They both presented with early morning tonic-clonic seizures. They had a very similar EEG. In their early 20s, they both developed psychosis. It says two things. Epilepsy and comorbidities do exist, and I know Dr. French talked about that. They're very important things to consider. But it really was the first signs, and he studied many of these twins. There's some other twins. Actually, we contacted one.
There were some young girls who had absence epilepsy, and we managed to track them down with my colleague Sam Berkovic. You know, it's just amazing to see the story they've had over the last... This is what? 80 years of advances in genetics. What is it about epilepsy versus all the other disorders, neurological disorders that have clear genetic mechanisms? There's common disorders like migraine and depression, and very common, and epilepsy that fits in that middle category of common, and you saw the large numbers that Dr. French mentioned, and then the not so common. But what is it about epilepsy? If you look at it, you know, the tribe has spoken. You look at.
This is the mention of the word epilepsy or seizures associated with genetic conditions in what's arguably the most comprehensive database of human genetic disorders, the Online Mendelian Inheritance in Man database. You simply look at the occurrence of that, and if you compare it amongst all the neurological disorders and even amongst all other diseases, the number of mentions and the number of papers and the number of genetic findings is so much higher in epilepsy. If you aggregate those two boxes, you know, you've got a multifold increase in the amount of activity in that space. The field has done this for us, and they haven't done it because they wanna crack epilepsy. They've done it because epilepsy is yielding its secrets.
Of all these disorders, the genetics of epilepsy is coming more readily than it is for these other diseases put together. That's an amazing opportunity there in this knowledge because there's a huge database of knowledge here. We're starting to learn so much more about the architecture, and I'll touch on that in a second. When we look at all the discovery, and there are hundreds of genes now have been implicated in epilepsy. If you look at those, what's interesting, there's a lot of complexity. Oh my goodness, how do you deal with 100, 200 different things? Each of these genes has got multiple mutations, et cetera. They are starting to fall into certain classes. Some that might be obvious.
You know, an ion channel makes sense because the brain, for epilepsy, you know, the brain is a moment-to-moment machine. Epilepsy emerges in those very short time frames. You change the level of excitability, and you can quickly change the brain state from being normal to epileptic. Ion channels and synaptic proteins participate in that in the short term. But then there are longer term things that happen. The mTOR pathway can drive cortical malformations. A lot of these things, and we'll talk a bit later in Praxis around tuberous sclerosis, which is a change in the structure of the brain. That region and those little tubers are epileptogenic zones. Then we're thinking about those. Chromatin remodeling, and how do you change DNA in the long term? We're starting to see patterns.
It's really important to see patterns to help you guide your decision-making. For which targets do you engage with? Why do you engage with those targets, and how do you engage with them? How do you use that knowledge to increase success in delivery of drugs for our patients? That's something that drives us, something that I live and breathe daily, and I've been doing that for as long as I know. I'm just, as I said, so delighted to be in a team now that wants to work on that vision, share that vision, and make it happen. When you think about almost any genetic disease, this is sort of a template, if you will, for how so how does this disease work? What, you know, what are the genetics?
There are basically four boxes, and I guess those of you who've been to business school, which probably a lot of you here, you know, a lot of things look like this. Which quadrant do we think about? On the bottom axis you've got, well, is it a common genetic mutation that we all have single nucleotide polymorphisms? We all have these things and some of them are very common, and we share them, and the collection of those determines how tall you are, how, you know, how smart you are, how high you can jump, all these things. Then there's how strong is that genetic change? What's the effect size of that? And that's what's on the vertical axis. Now, where does epilepsy live in? I've been working in this field for 25 years, and when we started, all we had.
There were like four eras of epilepsy really. There were the twins, then there were the families, then there were the sporadic cases, and then there is the common population epilepsy. Four major chunks of discovery. The last two are the two that have been that founded Praxis, and I think the very last one I'll talk about later is the future of Praxis as well. Where do we sit? If you look at the top left quadrant, families sit in that quadrant. It's a rare family, a single gene inherited in that family causes epilepsy. If you're unlucky enough to get it from mom or dad, you've got epilepsy. It's a rare gene. It's not in the general population, and if you get it, you get epilepsy.
We would say that's a rare gene with a large effect size, and it captures rare monogenic epilepsy. That would this first era was twins, something genetic. The second era was families. We're finding rare genes, but we can't really. I actually started my involvement with biotechnology in around 2000 for a small Australian company called Bionomics, where I took care of their CNS research on a part-time basis to try and take advantage of that. But it was very quickly apparent that these genes weren't common. These families were rare as hen's teeth. We couldn't it wasn't actionable. It was almost too early to use that knowledge to move forward. But what happened in that third era where we started to understand the causes of sporadic, rare, and very severe epilepsies.
Back in quadrant one again, that's where those rare diseases that Dr. French was talking about gave birth to Praxis Precision Medicines. We started to realize that there were a whole slew of genes, and there's been, you know, around 200 or so now that have been identified, where mutations in those can give rise to de novo epilepsy. The parents don't have the mutation. It's a random event that occurs, and there's a mutation in there. Then this child now unfortunately has a very severe epilepsy syndrome. That started to crack because the sequencing technology got so cheap. We could sequence whole exomes, whole genomes, parents, et cetera, and find these genes.
Now, but what's happened now, and this is really very recent, is that we're starting to say, "Well, what gives rise to common epilepsy? In the rest of the 90% of the population of people with epilepsy, is that other rare diseases? Do they have single gene that's causing it? What's actually going on? We have no..." It's only now we're getting to understand that. What it is, like the same thing that determines height and weight and all the things that are human features, it's the accumulation of common genetic variation that's driving the emergence of epilepsy in the population. The same thing that could make you tall, the same potluck of genetic combination can give you epilepsy.
That's really important to understand that because once you understand that you're much, much better positioned to know how to act to reverse it. I think it speaks, and Dr. French so beautifully set that scene for that in saying, "How do we..." It's not just random mechanism, and we can all be very clever in the lab and figure out, oh, that's an interesting mechanism. How do we take advantage of that? How can the genetics tell us? It tells us how the system breaks to get epilepsy. There's knowledge in that on how to correct it. That's
The next era, I think, and something Praxis is actively positioning for, doing the thinking, doing the networking, understanding how to act on this new wave, there's more and more data is gonna come out in the subsequent months from now, and we're very much primed to be at the forefront of understanding that data and acting on it for the benefit of our patients. We went from that, the twins of William Lennox. This is sort of where we are today, what the genetic landscape of epilepsy is. What you can see on the left is the rare monogenic epilepsies, those single families I mentioned. The sporadic cases in these kids that have a very powerful mutation that gives rise to a very severe and debilitating epilepsy with no recourse.
There are no drugs that are useful for these kids at this time. As you move across, you see the common polygenic epilepsies that are due now to the accumulation of various amounts of genetic variation that we all possess. It's just the accumulation of the wrong set of those common genes that give rise to the epilepsy. To the very right-hand part of that which is 100% acquired epilepsy, traumatic brain injury, a head wound, a tumor, cardiovascular event, some environmental toxin then gives rise to a 100% acquired form of epilepsy. I think this captures. Then the prevalence is a guide. It's not exactly to scale, but it's just a guide to say where the sort of relative numbers of patients are in this spectrum.
This is a very powerful area, and we've been using this at Praxis since day one in engaging with. If you look at our pipeline and think, "Oh, well, how do you get into depression? How do you get into essential tremor?" It's always been informed by our understanding of genetics of epilepsy 'cause genetics and epilepsy shine light on genes that are critical for brain function. Whether that's disease or not, the genetics is incredibly informative of that. Just take for an example our PRAX-114, which is a GABA PAM. I mean, at the time, I think I'm the longest-serving Praxian at this point in time. That's a dubious honor. This means I'm old. I think I'm the oldest person at Praxis. We're both. Yeah, thanks, Marcio.
You never let me forget that, do you? You know, PRAX-114 is a neurosteroid, a GABA PAM. We know and we knew some 10, 15 years ago that this gene, the target for PRAX-114 is mutated in epilepsy and gives rise to a very common form of epilepsy. Wasn't a common mutation, very common form of epilepsy. We know that same gene and that same system is involved in genetics of mood disorders. Catamenial epilepsy is a form of epilepsy that females get during different times of their menstrual cycle, and that's due to fluctuations in the levels of neurosteroids that act on this particular gene. It can give rise to mood disorders, and it can give rise to epilepsy as well.
We knew that a lot about the genetics of this, a lot about the neurobiology of this, the decision to take it into that direction was very much informed by that knowledge. We knew also, and I'll show that later, that it's a good antiepileptic drug. It actually stops seizures. That gives us a lot of validity from a biological perspective that it's got the actions that are consistent with a mechanism that would be helpful in depression. Similarly, for PRAX-944 , I won't go through all the gory details of that. Very similar for that. A genetic story, a neurobiological story consistent with. You know, this is a gene that's important for sleep because there's a certain rhythm that's generated in the brain that makes you sleep.
That same rhythm can go awry and cause a type of epilepsy called absence. That same rhythm occurs in other parts of the brain responsible for movement. Our neurons, the networks that are formed by that are very sensitive to the function of these types of calcium, T-type calcium channels. That was part of that. In a more obvious space, when we look at our rare epilepsy programs, well, they sit firmly in the left-hand part of this spectrum. They are deliberately and expressly designed to reverse the effects of a genetic lesion that causes the disease, and that's almost the simplest case. You have a gain-of-function mutation, can you make a drug that reduces that?
You have a loss-of-function mutation, can you make a drug that increases the activity of that gene to directly counter the causal effects of your seizures and your epilepsy? That's so important because, and I think again, Dr. French said it so beautifully that we are good at symptomatic, at developing drugs that give symptomatic relief. We do not achieve the reduction of the attendant comorbidities when we're so focused on symptomatic relief. When I did my training, the way to develop an antiepileptic drug was to get a cat, to buzz it with electricity and give it the drug and see how much you have to turn up the knob on the electricity for the seizures to reemerge.
That gave wonderful drugs that stopped seizures, but that had nothing to do with the root cause. Each of these agents, each of these things, we know precisely the genetics that we're targeting. We know exactly where we're going, and we're trying to reverse it. That was the mantra. That was the founding of Praxis Precision Medicines, why we wanted to do it. Now, there's a sort of a third bucket of that because starting with genetics as a shining light on our understanding of neurobiology, we understand. In this case, we're looking at focal epilepsy with molecules like PRAX-628. We know. I'll talk a little bit about that, about what we designed into that molecule in order to make it specific for that particular type of epilepsy.
We're using the knowledge, and we have specific ideas that emerge because we know why seizures emerge, what causes excitability in a neuron, and therefore, what is the point of sensitivity? What's the Achilles' heel of that process? Can we make a drug that targets that weakness? Now, this is the future I mentioned for Praxis, this big area in the middle of common epilepsy caused by aggregation of common genetic variation in the population. And we're thinking very strategically now about how do we use this to develop the next generation of drugs that will do both things, stop the seizures cold, but also because they're tackling root cause mechanisms, have a much stronger probability of tackling all the comorbidities. We're not gonna put that fellow to sleep now in order to stop his seizures. That's something that's very important to us at Praxis.
You'll see all the different ways as I speak later in the session about how we're thinking about achieving that balance between proper efficacy, trying to do as much for the comorbidities whilst not entering into that black hole of toxicity. This sort of overview, and I think we're gonna pause here for a quick break and a coffee break. This sort of overview, the three broad strategies at play at Praxis for how we think about developing drugs, all of these informed fundamentally by a genetic mechanism. Each of them can also inform around an indication expansion when we're ready, when the time's right, when the opportunity's there, how do we take this knowledge and move into a different space?
As I said, epilepsy is the sandpit on which whole slew of brain functions can be revealed, and we really wanna play in that sandpit, and we wanna have as broader impact on human brain health as we possibly can. I think I'll leave it there for a short break. We'll have a bio break and a coffee. Thanks, everyone.
Thanks, Steve. I think he means short, so maybe you're gonna do like a five minutes break. Just stretch, get some coffee, come back, and then you're gonna talk a lot more about how the action from this conceptual framework gets drugs into the clinic and helping patients. Back in five or so.
Hope you got a coffee and a bit of a break. As I said, I talked a little bit about our broad thinking and our strategy in the previous session. What I wanna do now, briefly touch on how, you know, our model of how we get things done, and then just go a little bit deeper into several programs to give you a flavor for how Praxis actually thinks and conducts and executes on activities. This slide, there's two aspects to this slide, really. The top part and is one of our four pillars that Marcio showed us, and it really speaks to our thinking in the translation space. We think translationally very, very early. When we're thinking about a program, we think about the patients, who are those patients gonna be?
How do we identify them? How do we align the genetics, the therapy, and the patient group at the same time? Because that speaks to plausibility, feasibility of moving forward in those areas. We have a whole slew of models that we need. Epilepsy emerges at a very high level. There's a brain, high brain-level behavioral seizures, high-level electrographic seizures, but we start from single genes. We need models that enable us to connect the dots between those different scales, so from the molecular to the neuronal, to the network, and to the whole brain and behavior. We do that. We're interested, very much interested in biomarkers, whether they're electrical, whether they're biofluid. Even this concept of endophenotypes, changes in behavior or in performance of something that's not part of the core phenotype, but gives you a sign of that disorder and a sign of efficacy.
Patient stratification, genomics, informatics, functional genomics. It's a lot. It's a lot for a small company. We're very lean, we're very efficient as an organization, and we think collaborations are the key to us expanding our footprint. As you can see below, just a sample of the organizations that we've got some deep and collaborations with that help us with our mission. We think this is really important for Praxis to move forward rapidly, to move forward efficiently, and not to have so much inertia that we get caught in an area. We're caught in a box because we've developed and we've put too much internal resources. We built the laboratories and everything, and then that becomes a boat anchor. We need to remain nimble so that we can move, and we've solved this, we think, with this approach.
It's not slowing us down. We all work hard. All the teams work hard. We have an amazing team of people who reach out and collaborate with these people, so we're very blessed in having a highly functioning science team within Praxis, and a clinical team that can pull this off. I'm gonna touch on the three strategies that I left you with in the first part of the talk. I'm gonna give some examples of programs that have emerged from each of these three strategies.
Always informed by genetics, but have moved forward into programs. This one, I'm gonna focus on nodes of pathological convergence informed by genetics. It's always been the mission: how do you reduce the complexity of, you know, we've got 20,000 genes in the human body. Each of them can break. They can break in different ways, give rise to different disorders. Sometimes it's good to. You know, rare diseases, we can tackle them one at a time, but in many cases, we want to understand whether or not from the many come the few. Does it converge to a single point? Is it a network? Is it a neural network? Is it an intracellular signaling network? We can do one drug, one process can subserve a lot of different therapies.
A really important area is voltage-gated sodium channels. Historically, epilepsy has many of these. These drugs emerge whether you're screening phenotypically or mechanism-based. Why? Well, the genetics has told us that mutations in these three sodium channels, NaV1.1, NaV1.2, and NaV1.6, is the cause of many, many rare diseases in epilepsy. Unequivocal mutations cause disease. We also know that these genes are starting to emerge in that common gene issue that's in the common epilepsy patient. We know that NaV1.1 and NaV1.2 are powerful signals for developing epilepsy in that other domain. Really important genes. Why are they important? Well, this is a little cartoon of a nerve. There's a particular part of the nerve where the brain is an electrical organ.
All the signaling, the way it speaks to itself in the short term, while I'm doing, talking, moving, everything's happening electrically. The slow stuff, this chemical signaling, the structural change, that's all slow. That's when you learn how to play a piano. You have plasticity. That takes a long time, and it's impossible for me, but it takes a long time to do. That's a different process. Moment to moment, and the way that our behavior, our mood, our depression, all of these things that can be governed by the moment-to-moment function of the. These channels are the source of that signaling. Essentially, they are like a spring-loaded faucet. You whack them with a hammer, and they give a spurt of water, and then they rapidly shut. That's the brain has to talk.
Like when we know about computers having clocks, and they're measured in billions of cycles per second, gigahertz. The brain's got its own clock, and it's determined by the function. What's the fastest biological process in the brain is an action potential. That's that little squiggle, that little brief squiggle of electricity that occurs when these channels open. That's about a millisecond. The fastest clock we've got in a single neuron is about 1,000 times per second, and that very rarely is that reached. That's the basic clock. That determines the basis of everything. You can understand in an epilepsy, those neurons are going haywire. They're firing at speeds they shouldn't be operating in, so they're in new operational envelopes that they shouldn't be in, driven.
These channels, either they're directly causing that or they're bystanders participating in that process, so very, very important to our signaling. They also can break through genetics. They can break through being in the wrong place at the wrong time and being activated in a certain way. A really, really tiny thing, this is like the old story about a butterfly flaps its wings, and it causes a tornado in China. It's the same sort of thing. This is a tiny change in these channels. I mentioned that faucet that you whack it with a hammer, it springs open and then springs shut. If that faucet doesn't close and it drips the tiniest amount of water, that causes a problem in the brain. You can see here that little black line is what a normal channel does.
You can see the blip is the blip of water when the thing opens and rapidly closes. The red is the dripping of the faucet. It's called persistent current in a sodium channel, and it's a tiny amount of current. We see it in genetic mutations. We see it in channels that have been subject to a lot of activity, such as in epilepsy, and it causes a major impact on excitability. We think it's a really important node. When you're thinking about how do you deal with the pathology caused by sodium channels, you have to deal with this. You can't ignore it. Happens in patients' SCN8A gain-of-function epileptic encephalopathy case. You can see the baseline on the left. You can see that persistent current in the patients on the right. It happens in SCN2A patients.
The black at the top, the fast inactivation shuts off. On the red, there's a constant on. Persistent current on the right is the way that the biophysicists display it. Compare the purple to the black. What does this mean? What effect does it have on the way Praxis thinks engaging to make a drug? You can think about sodium channel drugs, and a lot of companies and others think about subunit selectivity. We're gonna make a 1.6-specific agent because we know the 1.6 channel's important. Nonetheless, even if you achieve subunit specificity, you still have the problem of overengaging that channel. You can't turn the volume completely down on the television and still listen.
You still need some volume, but you don't want it to blare, and that's the problem, the same problem with the nerve in a disease state. It's blaring. It's going too hard. You wanna do something that turns it down but doesn't stop it. That's it. Even if you've got subunit selectivity and you've got this drug engages with all the channels, it's still gonna turn the volume off for that particular thing. We think in functional terms. How do you stop those channels that are participating in the nerves that are overly activated? The channels contribute to that overactivation. We know from an electrical perspective, channels change their function, persistent current, all of those things contributes to overexcitability of neurons.
Can you make a drug that's tailored to the high activity and allows the normal activity to go through. That's what that graph is showing. We think of nerves have this thing called an input-output curve or a transfer function. You stimulate them, they do something. Now, generally, in the diseased state, a little bit of stimulation does too much. So you've broken that cycle, you can. That's what that black represents. You've got too much activity for the input that you've got. We do want the stuff on the left to happen as normal so that we, our cognition, our movement, we're not sedated, all those other things, all those things that Jackie said. That gray box is her black, her black hole of toxicity that she couldn't remove from the presentation. How do we avoid that?
Well, if we can get rid of the persistent current, that's one way of doing it. If we can have a drug that binds rapidly and unbinds rapidly from the channel, that's another way of doing it, because your drug needs to interact with the channel in real time. Some drugs bind and latch on and take a minute, half a minute to drop off again. They don't have the right cycle time to be tracking the activity of a neuron. So these were two very important criteria that Praxis considered to produce functional selectivity. We think that with the focus on functional selectivity means you can make a drug that dampens down that hyperexcitable state, allows normal flow, and we should enjoy more tolerability. Dr. French mentioned how important it was to have tolerability.
This is one of the mechanisms at Praxis. You know, this is what we wanted to do, and I'm pleased to say we've done it twice. PRAX-562 and PRAX-628 are two examples of how we started with an idea and we've delivered two molecules that do this. Let's have a look at some of their properties relative to other molecules. This is some of the areas that we're gonna put in for PRAX-562 . SCN1A gain-of-function, I mentioned, I showed you that. Those patients have persistent current, have too much neural activity. SCN2A, those patients have persistent current, have too much neural activity. Tuberous sclerosis, which is an interesting one. It's a cortical malformation, and it gives rise to a focal seizure. It's a very interesting malformation. We've done a little bit of work on the so-called these tubers that are produced.
They've got a core in them of really weird neurons that are mega-sized and have an odd behavior electrically. Now that core, we know surgically, in some cases, you remove that core, you can actually have a major effect on the amount of seizures. We wanna try and again stop the activity of those neurons from entraining the whole brain, going from a partial epilepsy to a generalized epilepsy. Now, molecules like PRAX-562 are some of the best anti-seizure medications I've ever seen, and I've played with a lot, put them in a lot of different models. These things stop seizures cold because they're so focused on this initiating event. We think they're very well-positioned to impact these tuberous sclerosis.
Overall, we're looking at about 10,000 patients here in this collection for targeting with PRAX-562. Still within the rare envelope, but we think we're gonna have huge benefit to be brought. Now, these are the old mainstays, drugs like lamotrigine and carbamazepine that have been around for many years. Two important figures there to look at, the red curve and the black curve. The black curve is how well do these drugs block that persistent current, and the red curve is how well do they block the other current that tends to lead to toxicity. When you start to hit too much red, you get into the toxicity region. The other thing to look at is where they are on the dose-response curve, the potency. Look at PRAX-562. Huge left shift.
Its sensitivity to persistent current is a two-fold better than the nearest competing molecule and many fold better than many other molecules that are currently on the market. Its potency is many fold greater than anything else on the market. That difference between the red and the blue curve is really important. That potency of the molecule, where it lies, is really important because as we all know, less molecule is always gonna be less toxicity for all the other reasons. We think it's got an incredible properties. It's binding. It's the fastest binding sodium channel drug I've ever looked at.
We're lucky to have Chris Kahlig as part of the team who's worked on these sorts of molecules in the past, and he can attest to that incredible binding kinetics of this molecule. It really differentiates at the biophysical level, it differentiates how it affects neurons, and we believe it's gonna differentiate on what it does for patients who are taking this molecule. Bernard will talk more about that. This just talks about the potency difference. Look at that. All the other drugs on the right, PRAX-562 on the left. Hugely more potent, big change. The ratio of that, essentially that red curve to the black curve, that persistent current versus the other current, 60-fold.
We think that gives an enormous therapeutic window, when you have that sort of difference. You can do what Dr. French said you need to do. You hit the wall, you wanna go that little bit further with your drug, but you can't. You can't because you hit toxicity. These are the sorts of properties of the drugs that we wanna develop and deliver that allow you to break through that barrier between efficacy and toxicity. Now, how well does it work when you look at it? On the left is a seizure model, maximal electroshock. We won't go into the details. It's a mainstay in the industry. It gives us good benchmarking against other molecules. You give this drug to that model 2 mg/kg produces a 50% reduction in this assay.
On the other hand, you use, you know, how do you demonstrate neurotoxicity? One of the very common and simple ways is to see whether the animal's movement and behavior is impaired by dosing it up, and this is a spontaneous locomotor assay that does that. We dose up the animal, and we see does it get drowsy, does it move less, and you have a look at the dose response of that. The 50% point of that and the 50% point of that gives you this idea of efficacy. We've got about a 17-fold therapeutic index, which is massive. That's massive therapeutic window there. We also know that it works in genetic models.
The two patient populations that we wanna give the drug to, when we give her this drug, we can completely abolish seizures with these patients, with this molecule in the SCN2A and SCN8A models. Similar to the patients, these are rodents, but they got the genetic changes that cause their channels to play up in the same way they do in humans. Hugely efficacious. Also keeps these animals alive longer. Not only does it stop the seizures, but a lot of these animal models over time just have a terrible seizure and die. This drug keeps them alive, and you can see on the right, you withdraw the drug, then they start dying again. Excellent evidence that it's having this so-called disease modifying. It's going beyond seizure control. Interestingly, because this is.
I mean, it's such a good anti-seizure medication because of its profile, its envelope of behavior. We put it into some potassium channel models of rare epileptic encephalopathies, and it was very effective in those. KCNQ2 on the left, KCNC1 rodent model on the right. This molecule's effective because of how it acts. It doesn't have to be a mutated channel to work, but it's acting in a way and at a part of the neuron that gives us precision, not that one-to-one correspondence of a gene, and we're reversing the effect of that gene. It gives us precision because we have anatomical, and we have biophysical, and we have neurological evidence for why this is a point of sensitivity, and we're tackling that point of sensitivity. PRAX-628. This is the associated molecule.
We've developed two for two different areas that we're targeting. Adult focal epilepsy with PRAX-628. About 2 million patients in adult focal epilepsy, and these are the patients. You'll hear more from Dr. Friedman about the tough time these patients have in getting medications to change their lives. We think PRAX-628 and Bernard will talk more about the properties of the molecule that make it better for patients. But we think it's got the right properties, the biophysical and the neurophysiological properties that are gonna be of high benefit to people with focal epilepsy. When we compare it to PRAX-628, we see some differences in its biophysical properties. But it's still very potent.
It still has an excellent ratio of tonic to persistent current block. It's also got PK differences that are more suited to a broader population for daily dosing. PRAX-562 has got a longer half-life. As we know, as Dr. French mentioned, for a lot of kids and people that'll be taking this in the encephalopathy groups, compliance is really important. Here, the effects of missing a single drug will be less because the drug, the peak to trough ratio is much less for a molecule like this. Has very good properties for giving level exposure levels that can be very beneficial for patients. PRAX-628 also isn't metabolized on a six-hour scale, which is great.
Again, slightly more rapid benefit. Bernard will talk in more details about this in his session. Again, like the way we did the assay for PRAX-562 with PRAX-628, about a 17-fold therapeutic index again. Efficacy on the left, tolerability on the right. Good separation of those two things. Just think, 10-fold difference is great for a drug. We've got 17-fold. I'll leave that section there. I'll move to what I think is maybe the most obvious approach, which is focusing directly on underlying genetic defects. This was the founding principle of Praxis around precision medicine in rare disorders. It's real. These are just some of the programs that we're working on. In each of these cases, the disorder is caused by a mutation in a single gene.
There's lots of different mutations 'cause there are private mutations that these patients have. There's some recurrence, and that's just random. I mean, not inherent. These kids are so sick, they don't grow up to have families. They can't pass this gene on. They have these random mutations that either turn the gene on more or turn the gene down. Fundamentally, it's too high or it's too low. It's gotta be in that Goldilocks zone in order to work properly. Our approaches, whether they're ASO or whether they're small molecule, are specifically designed to push it back into the Goldilocks zone. How do we do that? I'll talk a little bit about those. PRAX-222 is an ASO that we've developed in collaboration with Ionis for SCN2A gain-of-function epilepsy.
This is SCN2A, I mentioned before, is that sodium channel that's in the axon initial segment, and it's got massive gain of function in these kids. Works too hard. They have seizures. They have other mood and behavioral disorders, and they have a huge impact on carers and families alike. And we're very, very committed to helping this patient group. What do you do? Well, you can use an ASO to reduce the amount of the channel. Antisense oligos are quite flexible in that they have lots of different modes. They can turn a gene down, they can increase the gene, they can increase the expression, they can change the binding of various DNA-binding proteins, et cetera. They're very flexible in the types of different modes that we can use them in.
In this mode, simply the ASO binds the so-called gapmer, and that targets that RNA for that SCN2A channel for destruction. We can reduce the amount of RNA, and we can do it with quite a lot of precision. This is a preclinical study that we undertook. You can see on the left different levels of ASO cause a different amount of reduction of the mRNA. You can see that very clearly on the left. We can titrate that. If we wanna knock down 20%, 30%, 80%, we can titrate that. Does it change the protein? Does it change the structure? On the right, you can see the two gray ones, which are our controls, the orange box, given the ASO, we reduce the SCN2A protein.
On the far right there, that's actually an image of that axon initial segment, the little, the white squiggle in the ASO control. You can see that the white's gone because we've reduced the SCN2A, and we've taken it out of the equation. It's not as much in the initial segments as it was. We've got RNA, we've got protein, and we've got immunohistochemical evidence that we are affecting the thing we want to affect. What happens when you give it to a mouse? These mice have been genetically engineered to contain a human mutation. This mutation is gain-of-function. These mice do not live much beyond 20 days of age. These mice, you put them on your hand at two days of age, and they're having seizures. One of those seizures will kill these mice.
We've never seen one go more than 25 days. That's what that gray bar is. This is a survival curve over time. All the gray ones that have got the control ASO are dead. At day one, we inject ASO into the brain, and we inject enough ASO to knock down the level by 50% or by 80%, and that's the blue and the orange. In those cases, you can see the rescue of the survival. Those animals are living longer. It's a tough time to be working with these animals because the brains are growing so much, so we did a second series of experiments where we gave a booster shot to clamp the reduction at the levels.
You can see what happens when you do that, and that's telling us that a 50% reduction in that middle figure, the animals live now or second injection at day about 35 or so, following their initial injection, those animals now live for 120 days, and only as the ASO gets metabolized do you see the disease re-emerging, and the animals start to die again. Similarly for the higher dose, as you would expect, more ASO on board, it's gonna take more half-lives down of metabolism before the knockdown level goes to the point where we're seeing seizures again. Hugely effective in these models, and we can even dose the animals later in age, which is also a question you have for people.
You know, what happens if you dose and the kid's already is a year old or two years old? You actually still see it. As long as the animals were alive, and they're right at that cusp now, four or five days before they started to die, and long as we can get over that, the cusp, these animals survive. Really lots of really healthy signs here that we can have a huge disease-modifying effect. When we started these animals, it wasn't just the seizures. All other aspects of this animal looked like a wild-type animal. You know, the movement and other behaviors, all these things were very, very similar to wild type, suggesting that we've not just stopped the seizures, but these animals by, you know, are indistinguishable from a counterpart, from a wild-type counterpart. Similarly for KCNT1, another devastating epilepsy.
This is a very interesting channel. It actually lives in that same initial segment region. It actually detects the sodium during the action potential and participates in the formation of the action potential. It's clear now that every single patient that's got this mutation has what we call gain-of-function. This channel works too hard. These patients have terrible intractable seizures. They're aphasic, they're immobile, they often sit in a cot, have hundreds of seizures, and die very young, and there's nothing we can do for them. What they need is an agent that blocks that channel, and that's what PRAX-020 is all about. Our program here, we developed a molecule, a small molecule that can inhibit that channel.
Here we're just testing that it can equally inhibit a wild type and a mutant channel because we know these kids have got wild type. It's obviously an autosomal dominant disorder. They've got a copy of each. Can we inhibit both? Yes, we can inhibit the mutant, so we don't have to worry about some complicated pharmacogenetic issue. What does it do to the seizures? Well, we've developed a model in collaboration with one of our partners. Again, they had the model, we worked with them, we dipped in, we got it done, and we moved out, went on to the next project. Here we can show that as we give the PRAX-020 molecule, we can essentially abolish the seizures. So when you engage this channel with the molecule, seizures go away.
We do EEG analysis. A big part of us is clinical, preclinical and clinical EEG is a big part of Praxis's thinking and our translation. Here we look at the spikes on the EEG. All, probably I've looked at probably 20 or so genetic models of epilepsy in mice. Pretty much every single one of them has EEG abnormalities in between the periods where the seizures are occurring. We call that interictally, and there's lots and lots of spikes. These animals are having 1,000 or 2,000 spikes a day. They're really good markers because you can measure this over a day. You're measuring 1,000 or 2,000 events. You give a drug, you see the reduction. Huge reductions in the level of spiking here.
The gray is the control, and the blue and the orange are dose-dependent reductions in the spiking. We're seeing changes in seizures, and we're also seeing changes in spike frequency. Some of the spike frequency changes, there are specific. The pattern of EEG in these patients is very unique. Migrating focal seizures with a frontal dominance. You might be able to use EEG measures in our target engagement and efficacy, and these are things that we're thinking about, and people work with people like Dan and Jackie, and Bernard's team is thinking deeply around how we would measure efficacy. I mean, in these patients. Really, and this is probably, for me, was an amazing moment in my scientific career in thinking, we always worry, are we just helping the seizures?
It's important, and Dan will tell us, and Jackie French also will tell us, "You have to stop the seizures." Yes, but there are other things that are going on in these patients' lives. These mice, untreated, can't build a nest. Now, it seems like a minor thing. Basically, you give them a tissue into their home cage, and they build a little bird's nest. You can see on the right, that's what they build, typical mouse, and they sit in that and that's their comfort. That's a natural complex behavior. It requires cognitive and motor skills. It requires the ability to draw on their instincts. This is an instinctual behavior. The mice aren't taught to do this. The animals with the mutation on the left can't do it.
They just can't build. You know what's remarkable? We give the drug, and they acquire this ability. Within two days, they're now building nests, and that's just remarkable. You take the drug off, and they can't build a nest. That ability to change this complex behavior that incorporates cognition in these timeframes, I've never seen that before, where you can turn off and on such a massive cognitive effect so quickly with a single drug that interacts with a single gene. We think, what does this mean collectively that within these patients, because we're going for root cause, not symptomatic relief, but doing root cause, we think the patients are gonna benefit across a number of different domains. PRAX-080. It's a molecule that, again, gives rise to this disorder called PCDH19 Girls Clustering Epilepsy.
It was a disorder seen in females, and when you see that, you often think X-linked. Females have got two X chromosomes. Males are XY. X-linked disorder. Quite a complicated and interesting mechanism of the disease that Praxis has utilized its detailed knowledge of genetics, of cell biology, and of clinical observation in order to come up with a what we would think is not an obvious strategy for dealing with these patients. The disorder is caused by the fact that when you've got a mutant in girls, in any given cell, you've got two X chromosomes. One of them is randomly turned off. It's called X inactivation. You don't have. You never express both. In males, we've only got one X. It's always on.
What happens, of course, if you've got a mutation on one of those X chromosomes, this cell will have the mutant, this will have the wild type. This cell will be wild type, the mutant, wild type, mutant, all mixed. That mixture of cells that are expressing different forms of PCDH19 is the reason behind the pathology. We know males that have got the mutation, 'cause they're carriers, don't have a phenotype. All their PCDH19 is mutant. They don't have a problem. It's only when you've got mixtures of wild type and mutant PCDH19 do you get a disorder. What's really important and what Praxis observed and acted on is that when you look clinically, there are some males that have no PCDH19. It's completely gone. They're carriers because they've got a null gene.
They can pass that null on to the female, and the female that's even got one copy without a PCDH19 and one with still has the disorder. Any mixture is bad and pathological. If you've got none, you're better off. Praxis' sort of proprietary approach here is to reduce all the PCDH19 in the females, take it down to zero, 'cause that's far better than having a mixture. We know that people survive well when you remove that. You can do that in a rodent. The males have it naturally. No problems. We think it's a really important. It just. I think it's a great example of how Praxis informed by genetics, and this is not just something we say, something we live and breathe on a daily basis. It's something that's ingrained into our DNA, no pun intended.
We've made progress on this with an ASO that's gonna remove this PCDH19. This is just on the left. It's the amount of knockdown of the ASOs that we've been screening so far. Greater than 90% reduction already. This program began about a year ago, and we're working hard now to turn this into clinical candidates, and we hope to have something for 2023. The final project will be SYNGAP1 loss of function. SYNGAP1 is another of the rare, and of the ones we've picked, these are the more common amongst the rare, if you want. There's about 1,600 of these patients diagnosed in the U.S., and these kids have intellectual problems, very severe behavioral problems, and drop seizures. I've been working with a few families in Australia of this.
Again, like all of these conditions, huge impact on the family completely dominates the family's life, looking after their two children with this disorder. It's a really important protein in the synapse. I talked before about ion channels. Protocadherin is a protein that's important for how neurons connect to one another. This is an important protein for how neurons talk to one another. Now, by removing that blue blob of SYNGAP1, by reducing that to 50%, that whole structure doesn't work as well. That's the receiving side of the synapse. A chemical transmitter is released from the neuron. This is the side that receives it. The lack of PCDH19 reduces a whole bunch of signaling with the synapse. You can't talk.
You're not talking the same language anymore from one neuron to the other. Again, the simple idea, can we increase the amount of SynGAP1? And when do you increase it? Luckily, a close colleague of mine, Gavin Rumbaugh, has been studying this. He's at the Scripps in Florida. He asked the question, "Well, if we turn the gene on later in life in a mouse," so it's the mouse has had the gene off. It's sick. It's got a phenotype. Can you turn it on later in life and restore its behavior? Yes, you can. SynGAP goes one, the EEG goes, issues are reduced. Seizures are reduced. Performance of memory is improved. That tells. It seems like a small thing, but it's a really important thing because we don't know.
The clinicians, the basic researchers don't really know what's reversible and what's not reversible. This is telling, and what we're seeing, we saw that with the KCNT1. We saw that the acute impact is what's causing that. It's not some chronic long-term change in the brain. It's the function of that gene now, here and now, that's causing the deficit. So many of the comorbidities could be reversible even later in life, and that's a really important thing, important information to have. We'll test this and understand this more clinically, but it's a really important thing to know that we're not up against it. It's not as if, well, there's nothing you can do. Kid's had seizures for six months. That's the end of the story. That's been the mantra in the field because we're conservative. We don't know.
I think the data's starting to come out in a very positive way. Again, now we've used an ASO again in this program that increases the amount of SynGAP expression. Different mode. I won't go into the details of how that's done today, but we can get almost a threefold increase with our best ASOs. More than enough. We only want a doubling. We don't need a threefold increase. More than enough to be able to treat. This is the sort of ASO, again, we're slated for delivery in 2023 for to move into clinical development. The sort of program that could just transform the lives of these patients. I'll give one last section of our thinking, and this is that final area of focus on implicated genes in common disorders.
Now, these common disorders can be epilepsy. These common disorders can be major depressive disorders. These common disorders could be movement disorders. How do we use our knowledge of the genetics to make the best decisions to enhance our probability of success, to get the best molecules that treat these patients across many domains of their disease as we can, and do it effectively, and as Marcio keeps telling me, do it time and time again. These are the two programs I mentioned before, PRAX-114 and PRAX-944. We call those imputed. The genetic evidence in common diseases wasn't available at the time we were making these decisions. We imputed it from rare cases. We imputed it from our deep knowledge of cell biology.
Now what's happening is that we are starting to see these, they're called GWASs or genome-wide association studies. These are things where you take a lot of patients. You know, they used to take 1,000 patients, and you say, "Well, for a patient with epilepsy, what have they got that's different from a patient that doesn't have epilepsy in their genome?" It was quickly apparent, and I was involved in these 20 years ago, you can't do it with 1,000. What's happening now, though, is they're doing it with 15,000 and 20,000 and 50,000 patients. Global consortia are being built, and every few months, there's another massive study that comes out. Some of the genes. What's happening, of course, as the studies get bigger and more powerful, more and more of the truth emerges.
Initially there's false positives, false negatives because they're not powered properly. Things are starting to be powered properly now, and that's what we're reacting to. We're in the midst of those. What I will do now, I will talk about how 114, what some of the evidence we used through that imputed mechanism. As I told you, it's in development for MDD, PTSD. I'm sure many of you have heard about Praxis' efforts in those areas. Totally inspired by our role is a study that I was part of in 2004, 18 years ago, showing for the first time that a mutation in the target for 114 to the GABA delta receptor, when it's got loss of function mutations, causes generalized epilepsy. Direct link.
As I mentioned before, there were a whole bunch of other studies done around catamenial epilepsy, premenstrual dysphoric disorder, all of it tied into the function. We've got direct links to behavior and epilepsy and neuroexcitability all driven by this receptor. A convergence, a perfect storm of information on which to make decisions that we think are reduced risk. What does it do? Synapses have got inhibitory. There's two major classes of function of neurons in the brain. There's the things that excite the brain and the things that inhibit them, the accelerator and the brake, if you want. That's how you achieve control in pretty much any system, the balance between those two things. Now, the inhibitory system has got two broad modes.
It either pulses the brakes off and on, which is called phasic inhibition, or it puts the handbrake on and leaves it on. That's tonic inhibition. Even though the handbrake, as you know, isn't as strong as a normal brake, if you keep it on a little bit all the time, it's got way more effect on your car than an occasional pulsing of the normal brake. That's tonic inhibition. Massive effect on the global function of the brain, and that's what's interesting about tonic inhibition. Our brains are bathed. GABA is the inhibitory molecule that comes out of the inhibitory neurons. It spills over, and it bathes the entire brain in a low level of GABA. It's around a micromole or so.
That low level of GABA interacts with these delta receptors and sets a baseline level of inhibition across the whole brain, and that's really important for setting behavior in depression, for setting sensitivity to seizures, and all sorts of things. That's what we're targeting with 114. We have predominantly, you can see here, we have a tenfold preference for that receptor versus the beta, the phasic receptor. That split is really important to these sorts of disorders. We talk about depression, these being global imbalances in neurochemistry, et cetera, and it's the global nature of this target and our ability. As we know, biology is local, but pharmacology is global. You give it the whole brain. This is a really good target 'cause those two things come together well. We think about that. Can we use functional selectivity?
Can we use gene selectivity to do precisely what we need to do to affect the disorder, limit the side effects, and get the efficacy we need out of the system? Sort of unsurprising when you think about the history, one of the things we did was just ask the question, is 114 a good seizure medicine? Yes, it is. This is showing in a chemically induced seizure that 114 stops the seizures cold. We know that it's a neurobiologically. It's obviously we're getting excellent target engagement. It's doing the sorts of things we'd expect it to do. Positioning from a genetics perspective, the links to behavior, excitability, and epilepsy, all of these things compel us to build a case for depression.
The final area I'll touch on, which is the future, and I won't go into this too much because we don't have anything to deliver today on this other than our acknowledgment. I think this is sort of phase II for Praxis. phase I was the rare diseases, the genetics and the understanding of rare disorders through monogenic epilepsies. Now, as we'll hear from our esteemed colleagues, we heard from Dr. French, and we'll hear from Dan Friedman, there's also a lot of people out there, a huge percentage of the patients with epilepsy that need better medicines. But we don't really know what's causative, and that's why we've been making symptomatic drugs. The genes are coming out. The GWASs are telling us, "Look, these 30 genes." I mean, everyone who's got epilepsy.
Our idea, and you can see them, and it's probably apt place to be doing it. These are called Manhattan plots because of the little skyscraper look. Those vertical excursions are the sort of statistical signal associated with whether a gene really is meeting the criteria to be causative in common epilepsy. You can see the more things that come across the top, and you can see a sampling of some of those genes on the right. It's the accumulation of these genes and these natural variations. All of our genes are different. We've all got natural variations in our genes, but it's this particular set of accumulation of variants that's giving you the risk for epilepsy. Our philosophy and our thinking is, "Well, what do we do about it?" We know that now.
We now have the ability to think about root cause. Is root cause dealing with one, two, three of these risk factors? A genetic mutation can knock a gene down or up by 5% to be risk. A drug can do 80% or 100%. Can you overcompensate a single gene and have a massive effect on the seizure propensity in those patients? These are the questions we're asking. These are the framework we're laying down for future decision-making to develop better drugs with higher probability of success. It's been done in cancer. Oncology has known. Oncology is or was 20 years ago where epilepsy genetics is today. Deep knowledge of genotype and phenotype in tumor cells, deep knowledge in what.
This is just mapping the activity, the commercial activity in programs that are looking at comparing what happens when you have an antibody, a bispecific versus a monospecific therapy that attacks one of the genetic markers versus two of the genetic markers. You see accumulated benefit as you tackle more and more of these things. Very similar concept and driver that we wanna do in epilepsy. How do we tackle that? These are the things that Praxis is asking. Some of the things are proprietary, our thinking, but we'd like to share more in the future around this concept. I'll leave you here with this, and I'll move pass the podium to Dr. Friedman. Thank you.
All right. Thank you for having me speak today. I just want to sort of talk here about my perspective as both somebody who's a clinical researcher studying epilepsy therapeutics and epilepsy outcomes, as well as a practicing epileptologist. I treat teenagers and adults in my clinic, and I sort of face day-to-day decisions that run into the limitations of our current therapeutics in my practice. I just wanna go through some of those, echoing a lot of the things that Dr. French said in her talk, but really talking about how it may impact individual patients and go through that. These are my disclosures.
I also work for the Epilepsy Study Consortium. You know, I share the passion of Dr. French for helping new therapies come to market. I'll start out with a case of a patient I might see in my office, and this is a 28-year-old woman, has a history of depression and presents to my practice after a ER visit for a witnessed convulsive seizure. The evaluation in the ER was pretty unremarkable. She doesn't have a tumor or a hemorrhage or anything that's emergent. Upon careful history taking, she's had occasional episodes of hearing a buzzing in her ear, then feeling confused, but she kind of blew it off as panic attacks.
We order an MRI and an EEG as sort of standard diagnostic workup for new onset epilepsy. The MRI shows a lesion in the left temporal lobe in Heschl's gyrus that looks like a focal cortical dysplasia, a developmental abnormality that in a neural migration and organization. An EEG that shows epileptiform discharges spikes in that same region in the left temporal lobe. Given this information, she falls into one of those 30% of patients that Dr. French mentioned that has an identifiable neurologic or structural cause for her epilepsy. The epilepsy is focal. The seizures start in one place. She is diagnosed with having epilepsy, which is just an underlying predisposition to have recurrent unprovoked seizures. The next step is symptomatic treatment.
That's what we have in our armamentarium right now. We want to prevent her from having more seizures. Why do we want to do this? We want to reduce her risks of mortality from seizures. People with epilepsy have a significantly increased mortality rate over the general population. Much of that mortality is specifically related to the consequences of seizures. People can die from accidents, drownings, and sudden unexpected death in epilepsy. We also want to reduce the sort of day-to-day morbidity from seizures. Even if the seizures are not fatal, people can have fractures, shoulder dislocations, burns from seizures. But ongoing seizures can also lead to long-term cognitive changes and neuropsychiatric changes over time. We want to improve overall quality of life.
We want her to be able to work, to be able to safely go about in the world, including driving and other activities that could be risky if she were to suddenly lose awareness. How do we pick from our symptomatic treatments? As Dr. French already mentioned, we have a lot of options to choose from, and this is sort of a timeline of the introduction, the marketing of various anti-seizure medications. You see a big inflection in the 1940s, where Merritt and Putnam introduced probably, which I think is probably the most successful predictive animal model in CNS disorders, which is the electrocuted cat that Steve mentioned.
That allowed for the identification of many, many compounds, many of which came to market in that time period. More so as we got a little more sophisticated about selecting compounds. As Dr. French mentioned, despite the fact that we have many of these options to choose from over time, the overall efficacy on the group level hasn't really changed that much with increasing the number of options. We have a lot of options. None of them are 100% perfect, but they do differ from each other in a lot of different ways, and mostly in ways of tolerability, off-target side effects, idiosyncratic side effects, and effects on comorbid conditions.
I'm going to go through sort of the decision-making process that I face day-to-day with patients with newly diagnosed epilepsy on how do I select which is the right symptomatic medication for them. We'll go back to our 28-year-old woman. She has depression and focal epilepsy. We know that some of our medications actually can exacerbate mood disorders. Probably the one that is most common to exacerbate mood in general practice is levetiracetam, but there are many others that can make mood symptoms worse. We want to cross those off our list in initial choice of therapy. Some of our medications don't work as well for focal onset epilepsy as they do for generalized epilepsies.
Those cross off our list, and we're left in this patient with these eight choices. But she's also on oral contraceptive, and she's concerned about weight gain. We eliminate the medications that have negative interactions with oral contraceptives, reducing their efficacy. Now we stick to medications that are also weight neutral. She also expresses desire to have children in the near future. Now we eliminate lacosamide, which doesn't have a great amount of data for its safety in pregnancy. We're stuck with really one drug to choose from for this woman. Even on an individual patient, there's a lot of room for improvement, giving her more choices.
I want to show this somewhat complicated flow diagram that shows all the ways that epilepsy and the epilepsies could affect what we really care about when we're treating patients, which is quality of life. Our target of therapy right now is seizures. You could see that there are many ways around the seizure box to get to a negative or positive impacts on quality of life as well. Let's start with seizures. As Dr. French mentioned in her talk, seizure freedom is what patients care about. They want to be on a medication that will make them seizure-free, and that is the biggest driver of quality of life.
This is an example from a pooled analysis of a randomized controlled trial of drugs for focal epilepsy, where the patients that showed any clinically significant improvement in quality-of-life measures from baseline were only the ones that became seizure free in the study. There was really no difference if you had no effect of the medication or it made you 75% seizure free. We want seizure freedom, and this is important for drug-resistant epilepsy, but it's also important for initial therapy.
You know, when I choose a medication for a patient, I wanna give them the greatest guarantee up front that it's most likely gonna work long term and not tell them, "it's about a 50% chance that you won't have another seizure." In terms of where we are in our landscape, you know, most in the drug resistant focal epilepsy population, most drugs, if you look at their clinical trials, look at the placebo-controlled phase, maybe about anywhere from 1%-5% of patients became seizure free in that blinded phase. The only real big difference that Dr.
French mentioned was the recent example of cenobamate, where at the highest dose, about 20% of patients became seizure free in that blind phase. That has really driven a lot of enthusiasm for cenobamate in the epilepsy community. Where is there additional room for improvement? The treatments themselves, as again Dr. French talked about, tolerability is a huge problem. A significant burden for patients with epilepsy. They are a big driver of negative quality of life. A big driver of medication non-adherence, second only to memory issues. You know, some side effects we, you know, are unpredictable, you know, that we can't predict by a mechanism of the drug.
Some are, and some are related to their mechanism of action, as Dr. French talked about and Steve talked about. You know, we know that based on their targets, you know, in the CNS, what kind of side effects, negative side effects we might experience, and especially in a dose-dependent manner. Fatigue, vertigo, ataxia, sedation, cognitive changes, tremor, mood changes are common side effects of many of our anti-seizure medications because they engage with targets that in circuits not involved in the epilepsy are involved in these sorts of processes. Another potential room for improvement in this example in this patient is teratogenicity.
A lot of the medications that we prescribe, we don't know their safety in the developing brain and their safety in children born to women taking them during their pregnancy. We have some data for older medications. If you look on the side of the chart, levetiracetam, lamotrigine, and oxcarbazepine are really the ones where we have the best data for safety in children born to women of childbearing age. Older medicines are less safe, and there's a whole slew of medications in the middle where we don't know about them.
It's important when we consider the treatment of women who may become pregnant, but it's also important because we give a lot of these medications to infants and children whose brains are still developing. Neurodevelopmental outcomes are very much understudied in our treatments. Another area where there's room for improvement in our therapies is the comorbidities associated with epilepsy. As Dr. French mentioned, the most common comorbidities that patients with epilepsy experience are mood-related, depression, anxiety, and memory and cognitive disturbances. As you move into more drug-resistant populations, the prevalence of those comorbidities become more common.
The old thinking was, well, this is just the effect of ongoing seizures on the brain or the effects of our drugs that we already said have a lot of off-target CNS side effects. We've come to understand that that's not the whole picture. There are plenty of examples of a bi-directional predisposition, let's say between depression and epilepsy, memory issues in older age and epilepsy. There may be shared risk factors because the same neuronal circuits that are not working and giving rise to the seizures may also be involved in regulating mood or memory. The underlying disorders that give rise to epilepsy may also give rise to the comorbidities, and that's another opportunity to target.
Because you could see on that comorbidity box, there are a lot of ways to get to negative quality of life, even if seizures are well controlled. Then finally, as Dr. French mentioned in her talk, there's a lot of opportunity, theoretical at this point, to treat the epilepsy, the underlying condition that gives rise to both seizures and the comorbidity. You know, all of our therapies are symptomatic. They don't address the underlying mechanisms. They need to be taken chronically, as she mentioned. We don't have the eraser that will remove that epileptogenic lesion, which, by the way, probably is genetic in etiology, not germline genetics, but a somatic mutation that gives rise to abnormally developed neurons in just one brain area.
No treatments alter the underlying mechanism that leads to the increased seizure susceptibility. We don't have treatments yet that can prevent the development of epilepsy and the acquired epilepsies that happen after a high-risk injury like a stroke or a traumatic brain injury. We don't have therapies that will make pharmacoresistant epilepsy now pharmacosensitive. Maybe take the patient who has to take three drugs to control their seizures only need to take one drug at a well-tolerated dose. There's a lot of promise in identifying new targets, better targets for therapy, including improved efficacy, including disease modification, including modification of comorbidities at the same time, improving tolerability, limiting off-target effects, and having predictable neurodevelopmental outcomes.
Despite the fact that we have 18 marketed drugs for the common epilepsies, as I sort of tried to show you, options fall short when we're faced with an individual patient that brings their own issues, their own comorbidities, their own unique life circumstances to the picture. These shortcomings present a lot of opportunities for differentia tion of new therapies. Thank you for your attention, and I will hand it off to Bernard.
Thanks a lot, Dan. We had great talks from Steve about how we leverage genetics and use translational tools, and from Jackie and Dan about the clinical need at kind of the patient landscape level, the cohort level, and the overall ecosystem. From Dan, at a very specific patient level, how you think about that, and how that drives selection of a particular drug. What I want to do now is bring all that information together and show you how we integrate that into efficient drug development programs, which we expect to have three for epilepsy in clinic this year. It's a really great time to be talking about it, and of course, that is why we're talking about it now.
Our PRAX-562 program is currently in clinic in healthy volunteer studies and is progressing really nicely along the lines of that very wide therapeutic window that we've described and Steven talked about mechanistically. The kind of cousin molecule, PRAX-628, we expect to be in clinic by the end of the year in healthy volunteer studies. We'll be developing that for focal epilepsies. Then PRAX-222, which is the one I'll start off with. As Marcio alluded to it at the outset, this is our seventh IND. I'll start off talking about this one 'cause it really in an incredible way exemplifies a lot of the principles that we've been talking about. We're very excited about this program. Let's talk a little bit more about 222.
Steve gave you the background, but as a reminder, it's an antisense oligonucleotide. It's designed to knock down SCN2A transcript and therefore lead to reduced protein and reduced excitability, and reduce seizures in children who have gain-of-function mutations in that gene. It will be an intrathecally administered ASO, and this is just like Dan was talking about, this is the need, true causal therapies directed at the underlying mechanism. Now, I wanna next turn to one of our key pillars, understanding the patient population. We went about this in a different way, so I wanna talk about this in some depth. We debated quite a bit, should we do like a big, kinda old-fashioned natural history study that would take us years to do? We decided not to do that.
We went instead with this kinda real-world evidence project, which I think has turned out to be very successful. Done it in SCN2A. I'll show you data in SCN8A, and this is reproducible and fast. I think it'll be a key part of how we approach these DEE programs going forward. But what we do is incorporate real-world data, medical record data. Not just text information, though. We're able to bring in EEG data and other kinds of complex, kinda very data-heavy measures that we're interested in. Of course, I do wanna thank the SCN2A patient community, the SCN8A community. We couldn't do this without their participation, without them signing up so that we could have access to this incredible wealth of data. This particular study in SCN2A involved 45 patients, really 45 families.
We're showing you here 15 patients, average age about 7.5. We're showing their seizure history. See, in gray is the seizures, and these are just the reported ones. In green are episodes of status. It's incredible. What's remarkable about this presentation is how dramatic it is. On average, these children presented with seizures, I think on day five of life. At about 80% of them, at some point, were having more than 10 seizures a day. It's an incredibly dramatic clinical presentation, difficult to manage from the outset. What you can see, take home from this slide is that these seizures don't go away. These are real-world data, meaning these children were optimally treated according to the best, you know, clinical drugs we have available.
Those seizures and episodes of status don't go away. Of course, seizures, as Steven Petrou described, are only one part of the picture here. Very important part, but there's profound developmental delay, and that involves different domains to straight up motor delay. These children can't hold their heads up. They can't sit up. They can't feed. Cognitive delay, which manifests in delayed, really absent language and social delay, the ability to interact in meaningful ways with family or caregivers. It's a very broad syndrome. It's hard to encapsulate in a couple of slides, but this one gives you a sense of the overall kinda clinical and medical burden for the patients and for the entire family.
In the first year of life, and you can imagine if seizures onset within the first few days, in the first year of life, these children were on almost 15 different medications. Most of those were seizure medications, about nine of them. They spend nearly 70 days out of their first year of life in the hospital, and then 100 days in total over those, on average, seven to eight years. Lots of procedures, recurring hospitalizations. You get the picture. This is a child and a family that's in and out of the hospital due to refractory seizures, taking lots of medications and having lots of side effects. It's somewhat paradoxical. You do talk to neurologists, and some will say they're satisfied with the standard of care, that they're working well, and there's sodium channel blocking drugs out there.
Clearly, they're not doing the job. There's no question about that there's a need for mechanism-directed targeted therapeutics. With that, I'm gonna transition to biomarker translational tools. Steve went over this really nicely. Between seizures, even in the animal models, there is a lot of residual hyperexcitability, and that shows up as interictal between seizures, epileptiform discharges. Kind of these, you know, epileptiform activity even though you're not having clinical seizures. Our team really nicely brought in these EEG data from that real-world study and looked at this is over years. What they were able to show was calculate what's called a, like a epileptiform discharge burden scale. It's how many of these discharges they're having and how long they last for.
What you can see in that histogram there is normal children, age-matched, don't have these. There is some very low underlying rate, suggesting that some kids may have a predisposition for epilepsy there. Children with SCN2A mutations continue to have these at a very high level throughout their life. That two key implications, two key take homes here. One is even between seizures, the brain is hyperexcitable. Comes back to, I think both Jackie and Dan mentioned it. Having drugs with long half-lives so you don't have breakthrough seizures is really important. Two, since this is persistent, you could use this as a pharmacodynamic biomarker to understand if your drug is having an effect without having to wait to count seizures.
There are plenty of seizures to count, but this may be really a more sensitive, continuous measure. We're actually doing an observational study to expand upon these data and use it as a lead in to our clinical trial. With that, I'll turn to the clinical trial. Marcio mentioned at the outset, and it was in our press release this morning that we've submitted this IND. It was really interesting. This has never happened to me, and I've been doing this for a while. At our pre-IND meeting, the FDA said, "Be more innovative, go faster, and do a seamless trial such that every patient has the opportunity to contribute efficacy data and has the opportunity to benefit." That's what we did. We submitted.
It is a complex study, and I'll compliment our team 'cause it integrates all phases of development, I, II, III, into a single trial. This is a single trial path to registration. We're sure the agency will have comments, but we're waiting to hear what they are. They've been very engaged, of course. What does it look like? The children will be children with gain-of-function mutations up to the age of 18, having continued seizures, which, as you saw, that's most of these children. We'll look at endpoints that cover all those different domains. Seizures, we'll look at EEG parameters, we'll look at developmental outcomes and social outcomes.
The trial, as I alluded to, is designed in three parts where there is a dose escalation, and we get an initial understanding of safety tolerability and the impact on seizures. That's followed by a confirmatory phase where we increase the number of patients and get a more precise understanding of safety and nail down the efficacy. There's a long-term extension, where we'll see about developmental outcomes, and we'll also see if we can expand the interval between doses to make it as convenient as possible once we're in the commercial and clinical setting. With that, I'll turn to talking about dose in a little bit more detail. This is something Steve mentioned a few times. Really focus. This is how you get it right. This is not a neurodegenerative disease, right?
This is a fundamentally a channelopathy. The neuroanatomy is intact broadly and at a cellular level. We're not worried about, like, some of the other problems that, like, recent ASO programs have run into, a neurodegenerative cascade, and you're intervening too late. If we get the drug to the right place at the right exposures, there's a very high probability that this should work. That's true for most of the programs, all the programs that we talked about. The other key thing here is that we know we can get very, very high levels of knockdown, like 90% plus in the cortex and other key areas, in the brain. We don't need to get that much knockdown. Steve showed you work showing 80%, 50% knockdown were efficacious, extended survival.
We've extended that, and we've shown at 35% knockdown, we continue to get efficacy. That's a good place for us to start. We know we can achieve that, and we've been very rigorous in how we've modeled this. Not just, you know, relying on, like, plasma concentration. We've our preclinical work and our tox studies have involved monkeys with intrathecal dosing. We use tissue levels of the ASOs as well as, of course, message for knockdown to generate this modeling. This just gives you an example of we can dose escalate, you see over the first six months or so, get to a target of 35%. It's actually pretty tight in terms of the variability for an ASO, and then maintain that level there with less frequent dosing on about quarterly intervals. Very rigorous.
We think this is the key and really different than, say, a Huntington's disease program where you're dealing with degenerating brain, and you need to get it, the ASO, particularly into deep targets versus cortex. Where are we with this program overall? We're enrolling that observational study focused on EEG, using it as a run-in to understand those interictal discharges. As soon as we hear back from the agency, we'll be initiating the seamless clinical trial. I'll turn now to the PRAX-562 program. We talked about this one before. Steve grounded us in the mechanism here, the relatively high potency for persistent current relative to peak current, as well as the use-dependent features such that you're only blocking sodium channels in hyperexcitable neurons.
That's what drives what we believe will be a really remarkable therapeutic window. We're already seeing that. I'll substantiate that in the next couple of slides. The other nice thing about five six two is it does happen to have a very long half-life, and so all we need to do is give a single dose, say 90 mg. It accumulates, and you end up with very low peak to trough. For children who are having a lot of recurrent seizures and underlying hyperexcitability, this is actually a really nice feature to prevent those breakthroughs if they miss a dose. Where are we with this program? There you go. We previously did phase I studies, SAD, two-week MAD, and food effect, and we've reported those. We had very nice tolerability.
We well exceeded our target exposures over two weeks. We showed on a biomarker of excitability, auditory steady state, that we had nice dose-related improvements there, reductions. The half-life, as we just discussed, turned out to be five days, so we decided to do a second study that was longer to get us to steady state, a 28-day study, and to also expand upon that ASSR work and understand it over time. We'll be wrapping that up over the next couple of months. That study's going very well, and I'll show you some really encouraging data about the therapeutic window. We anticipate in the second half of the year that we'll take PRAX-562 into proof-of-concept studies in children with SCN2A and SCN8A gain-of-function mutations. That's the targeted mechanistic genetic approach.
Steve mentioned there are nodes of convergence and shared pathophysiology with focal epilepsies, and the other cohort in that study will be children with refractory focal seizures due to tuberous sclerosis. Two ways of going, and it'll show both the targeted kinda genetic medicine approach, but also our approach to translating that into broader focal seizures and other kinds of epilepsy. Coming back to this TI issue, on the left here is a slide showing data from just day one of dosing. This is from our first healthy volunteer study. On day one at 90 and 120 mg, we exceeded the EC50 in the MES model, which is a commonly used epilepsy model. Now on the right, we have preliminary data, only a dozen subjects.
That's quite a few. Preliminary data from 28 days of dosing. I've never seen anything like this. As Marcio knows, I'm a little obsessed with hitting the maximum tolerated dose. It just gives me comfort that there's an end out there somewhere. We haven't hit that here. You see the EC50. We're reaching concentrations that are 20-fold above that without dose-limiting toxicities. I don't know if there's any other epilepsy drug that can do that. I'll say too, we're not seeing in healthy volunteers kinda on-target sodium channel blocking AEs you'd expect to see, vertigo, the nystagmus, ataxia. This is really consistent. Because we have the ASSR signal, we know we're getting drug in the brain. This just fits this wide therapeutic window.
I'll turn to the other patient population, children with SCN8A mutations. Same real-world data, and the visual, I think, says everything. These children have the same picture as kids with SCN2A mutations, incredible recurrent seizures, high rates of recurrent status. It's just kinda mind-blowing. It speaks for itself. The same picture about healthcare utilization, burden on the family, the child, and the healthcare system. This is the second genetic population that we'll be studying with PRAX-562. Again, this study is expected to start in the second half of the year, and I'll turn to our third program that we'll have in clinic for the epilepsies, PRAX-628. Again, this is related molecule to PRAX-562. Very similar mechanistically.
Preclinically, a very similar therapeutic window due to that, potency of persistent current and the use-dependent, features here. We designed this to have a different, metabolic path and a shorter half-life, making it more suitable for a broadly used drug, in focal epilepsy. It's predicted to have a 36-hour half-life, which is still long and we think will be helpful if people do skip a dose, but it's not, a five-day half-life. This drug is currently in IND-enabling tox. We expect to be healthy volunteer by the end of the year and then move into focal epilepsy from there. I'm gonna come back to this slide, and just, Marcio said we definitely don't like to brag or congratulate ourselves, but our seveth IND in the works, three epilepsy programs slated to be, in clinic.
The hypotheses here are panning out, which is really encouraging for us. The biology is panning out because it's true and it's real. We're excited to have the next two candidate nominations. With that, I'll turn it back over to Marcio to close.
I guess there is not a lot more to say after all these presentations. I just want to thank everyone before the Q and A, and just remind maybe to wrap, right? This is all very deliberate from the science perspective, from the business perspective, from the regulatory perspective. I know we mentioned number of INDs, was the interaction with the agencies, how deliberate we are bringing innovative patient data. We know there's a directive for the FDA to listen to patients, to understand the impact on their lives, to truly use the statutes on how they feel, how they survive, how they function. Data like our collaboration with Invitae and Ciitizen that was shown today, 10 years all medical records. That's what Bernard showed today.
It was not like, "Oh, give me a couple records here and there." We collected every single medical records in a 10-year retrospective manner, used machine learning to extract the data and put it in an unbiased way. We're not selecting when they report it. We're just showing when they report it, and it's devastating. It breaks this idea that, "Oh, if I haven't seen it because I'm the attending at NYU or at Columbia, it didn't happen." Nothing against us. It's just because they had to go to another hospital, and we were able to get that data. We're able to report this. The path for epilepsies is way more straightforward than for many other diseases from a regulatory perspective. That is the added bonus here to some extent, because we're gonna be able to, for example, with the FDA agreeing, using single trials for registration.
That's the aim, is to get there, not compromise. We're not compromising safety, we're not compromising efficacy, but really developing the best possible drugs for these patients. I think the need is absolutely clear. Now, with all of that come financial discipline. I'm not gonna repeat it again. I know it's top of mind for everyone. It's something I wanted to be very clear. We care deeply every single day at Praxis, and we're gonna continue to only advance the best drugs so we can generate the best return for patients, for everyone else. Just want to thank you all of you.
Most importantly, there are hundreds of patients that gave us the data that we've seen today because they gave their cells for a seed to grow or their mutations through like samples to be cloned or data for the natural history or observational or even in hundreds of patients in our clinical trials so far. They are the actual heroes, like you're just a little bit of puppets here trying to make this all work, and we will because that's what really matter at the end. We're gonna break for a few minutes, five or so, kind of rearrange here, get the Q and A going. Thank you so much for everything so far, and see you in a couple minutes. All right, I think we are ready to roll the Q and A. Oh, Laura is already-
Thank you, Laura Chico, Wedbush. On PRAX-222, and I guess the epilepsy programs in general, you have a mix of modalities, small molecules, ASOs. Could you talk a little bit about where I guess, the rationale for what modality makes sense in which indication? And then CNS delivery of ASOs specifically has been kind of a high bar to achieve. So could you talk about what features of the ASOs you're targeting, not only enable delivery but also distribution?
Yeah, no. It's incredibly important, Laura. And I'll ask Steve and Bernard to touch on that. I think the way we look into is it there? Is the target amenable? And what do we expect that to do at. And Bernard can talk a little bit about the distribution. We looked a lot into that. But please, why don't you start, Steve?
Yes. I think that's a great question. It's something we think a lot about at Praxis. Where is really important for a lot of these epilepsy targets, cortical exposure is really important, and we know that's one of the areas where ASOs naturally can achieve exposure levels from intrathecal administration. Particularly in some of the decisions we've made are looking at targets where cortical engagement is gonna be you know high probability of efficacy. We think biologically these are more tractable. As Bernard said, this isn't a genetic defect that sets off an entire complex cascade that's that has questionable reversibility. I think we've looked at that, so we think biologically we're gonna have efficacy. We're also looking at key collaborations.
Cerebral Therapeutics is one of them that has a catheter and a port system to enable human intracerebroventricular administration. We are exploring that as well with them for future programs. We're on top. We don't think every ASO program will require that, but where it is needed, we will have that option to tackle that head-on.
Yeah. Yeah. I'll just add, Laura. One of the reasons I joined Praxis ‘cause I like the idea that it wasn't a therapeutic modality platform company. It was a biology. The secret sauce is what Steve was talking about. We use the modality that makes sense for the target to get, you know, to do whatever needs to be done at that target, and to get drug there. You know, I think our modalities and delivery approaches will advance along those lines. Like, for example, we've talked a lot about we're doing, you know, genetic therapies with ASOs. We're not doing AAV gene therapy. For these ion channel targets, we don't want to. We don't think you'd get the right distribution. You know, you can't. They're not titratable.
I actually think it could be kinda dangerous to drug ion channels with AAV gene therapy at this point until you can regulate them better with cell-specific, regulatable promoters. I think we're choosing our modalities and our delivery approaches very carefully to match the program.
Not sure if this is on. Okay. I'm Tazeen Ahmad from Bank of America. To follow on the question of ASOs. Marcio, at your last job, you had some experience looking at ASOs over various indications. Beyond which today's topic is, which is epilepsy, how do you kind of view future potential opportunities? Would you look at Huntington's, for example, or related indications? To follow up on gene therapy, taking into account, you know, what you just said, Bernard, about disadvantages. There are still companies that want to pursue that route, who are pursuing that route in different types of epilepsies. Maybe just get a view from the panel on, is there a type of epilepsy that you all think might be more amenable to gene therapy? Would that be an area that you would consider going into over time?
Tazeen, the answer kind of Bernard gave is what I would start here for a previous question, right? Like, look into the targets, the biology, the distribution of the brain, and then ask how. Sometimes it's a small molecule, and for some of them, we showed today it's a small molecule. Other times it's gonna be an ASO. There might be a day that is an AAV or any other type of deliverable like gene therapy, not right now, and we can explore other bits on the why. But the hopes not a strategy has to stay true. I know sometimes I say that jokingly, but in this case, it's not. Meaning, do we actually understand what we are targeting? And as you saw by Steve's presentation today, we first ask the question, does this gene matter?
In some of the failures, like recently, I think that question was now resolved, right? For others, like you mentioned, like Huntington's, then there is repeat length and things like that that might not fully resolve. That answer is checked. That question is checked. The structure of the brain, the kind of knockdown that you might be necessary on that one is still not resolved. When you go to the toxicity, I'm gonna go back to epilepsy. We know what happens if you knock down a lot of SCN2A, and it's not pretty. There is a place that you have to stop. If I come here today and say, "Oh, we can just give this in an indiscriminate way," PRAX-222 as an example, it would be irresponsible.
The pharmacology, the biology, the basic like pharmacogenetics, have to play a role. Is that gonna be only epilepsy? Unlikely. It's very likely we're gonna be looking to other areas in the future. Right now, epilepsy makes the most sense. Now, to go back to gene therapy on the strict sense of gene therapy or like AAV-derived or regulation right now is just not possible in our view. It's a fine-tuning versus a hammer, and we need better fine-tuning.
I mean, that's the point with ion channels and many of these key proteins. Precisely where you express them, precisely how much you get is critical for the function. I think AAV, for many of these disorders, is too much of a hammer. When the technology improvements that Bernard and Marcio alluded to are with us, I think Praxis will be ready to look at that seriously and move forward.
Yeah. It all comes back to the points that Dan and Jackie raised. Like, it's about therapeutic window, right? That we get that with small molecules. You can't get that with AAV gene therapy right now.
Not today, at least.
Yes.
Yeah. I would just add that there may be types of epilepsies that are amenable to that kind of therapy. You know, probably the lowest hanging fruit are focal epilepsies.
Yeah.
As an alternative to destructive surgery, you can use a hammer in a very surgical manner. You know, but whether or not this is preferable to other therapies like neurostimulation that we have on the market or stem cell therapy that may be emerging, we don't know yet.
Can you just give me a little bit for Dravet and LGS? Do you think that the therapies available are sufficient or is there room for improvement?
I mean, I think there is definitely room for improvement for both. You know, I think fenfluramine was a big breakthrough for Dravet, but there's still plenty of patients who are on fenfluramine who are still having seizures. You know, there hasn't been an effect on the, you know, cognitive comorbidities and the gait issues and some of the other long-term effects of Dravet syndrome, in, you know, we don't think yet with fenfluramine. It didn't show that great efficacy in LGS, which is a heterogeneous disorder that is often due to a lot of the monogenic disorders that we've been talking about.
You know, lumping it as an orphan condition is, as a single entity, probably, is one of the reasons we have such sort of, you know, unsatisfactory outcomes with the therapies.
Ritu Baral, Cowen. Thanks for taking the question. First question's on PRAX-222. Bernard, what's left to talk about with FDA on that integrated trial design? Do you know sort of like the general sizes of the different stages? Where in that do you think you could generate that first quantum of seizure reduction data at the target dose? Generally what, you know, year?
We've had our pre-IND meeting and, you know, the feedback that I talked about in terms of the seamless study, and the parameters in particular that everybody can contribute both safety and efficacy data. There are other suggestions in there, but we submitted the IND last month. Waiting to hear. There's been some dialogue. Optimistic, but we're still waiting to hear. We know we'll be able to engage on whatever points they raise 'cause they seem extremely engaged in this particular program. In terms of where will we be able to start to see efficacy data. You know, we showed you that dosing paradigm, right? We start randomizing people, and they go into that escalation of dosing.
That's the first part of the study. You know, our initial target is 35%. It would take about six months of dosing to get there on what we've laid out so far.
Quick follow-up for Dr. Friedman. As you've laid out the unmet need, and as Dr. French laid out the unmet need, she talked about, you know, small percentage of patients getting to seizure-free, but, you know, maybe 75%-90% seizure reduction being, like, okay. Is there an absolute threshold for seizure rate where you feel that even if a patient hasn't gone seizure-free, that maybe you're stopping some of the neurological damage, maybe, you know, they'll start, especially children, sort of gain function, gain milestones? Is there like a number?
There's certainly not a number. I think in many of the epilepsies, you know, once you sort of reach 50%, you know, you begin to see add-on benefits on cognition, social interactions with the developmental encephalopathies, and other things. But there's incremental benefit. It also depends on the kinds of seizures. If you-- That's why sometimes looking at absolute seizure reduction, you know, is not always the right way to go because we know that, you know, convulsive seizures, tonic-clonic seizures are the most dangerous seizures, the ones associated with the greatest morbidity and mortality. Drop seizures in Lennox-Gastaut seizures.
If you could eliminate those seizures, you could make a big impact in people's lives without necessarily making them, you know, 75%. You know without achieving a 75% overall seizure reduction.
Last question, sorry. As you mentioned the tolerability burden of the current options that you have, what are the things that patients complain about the most, and what are you watching these new therapies for? You know, what are the potential additive tolerability issues that you don't wanna see?
The ones that on a day-to-day basis, you know, in clinic I hear the most are, you know, fatigue, irritability, mood changes, sleeplessness, double vision, unsteadiness. Those are the most common ones and often, you know, directly related to the mechanism of action. You know, phasic GABA inhibition or blockade and voltage-gated sodium channel.
Cool. Myles Minter from William Blair. Just on PRAX-222, have you disclosed your sort of target dose that you're looking to see with the intrathecal administration there to achieve that 35% knockdown? I'm curious whether it's up towards the 80 mg or above, which might raise those tominersen issues that we've seen in HTT lowering.
I'll take that one. I'll take the bullets. No, just kidding. There's no bullets there. We know where to start, and I think that that's what Bernard was guiding, right? The most of the dialogue with the agents has been where we would start, so far. It's fairly conservative, I would say right now. Before we disclose, we do expect they're gonna agree with us on. But we just don't know, and that I don't think would be responsible. Now, it is, I would say, lower than what one would expect where we're gonna end up, not only we're gonna start to reach 35-50, where I think is the sweet spot there.
There is general accumulation that happens, and then there's an expectation that we'll be able to move from a number of weeks between those to a much larger number later on on the treatment as well. Lower than the number you quoted, Miles, there, but I think right now should still, like, hold a little bit what it is. It is starting pretty low, let's put it this way.
Maybe on PRAX-114, we saw that in the slides. Why haven't we seen a trial started in epilepsy comorbid with depression? Are you waiting for Aria to read out on that one?
It, it's so-
Sorry for Miles.
No, that's a great question. We were joking about this a little bit the other day. It's discipline. It's probably the best word. It's overused a little bit as well. It makes a lot of sense to use PRAX-114 in epilepsies, as you saw, and a few other things as well. But it makes even more sense in fear extinction, on mood modulation, on anxiety, like major depressive disorders at this point in time. It's not the only compounds that we have in the class. You might take a look at our charts. There are undisclosed targets there that we might be looking into, different things. That is a unique proposition for us that we really don't believe it exists in the markets, that those drugs can be combinable.
While we don't like using a number of drugs, you could imagine for movement disorders, for psychiatry, for epilepsy, that when you look into the entire patient population, we could really treat a much larger number of patients by combining them. That's kind of half of your answer there, Miles. As soon as the positive results come in, that we expect five or six between now and the end of the year, the entire markets change a little bit as well, ability to have more capital available, more for the company, then we might change the strategy a little bit. Right now, we're gonna stay focused, keep the burn the way it is, keep the size of the company the way it is, so we can deliver the promise instead of just waste resource.
I think he asked.
Oh.
Oh.
Hey, Marcio. This is Doug Tsao from H.C. Wainwright. Maybe to start, Dr. Friedman, you sort of mentioned obviously the goal is to get a patient seizure-free, and that does not happen often. You know, most patients are obviously on polypharmacy taking numerous medications. How do you think about at what point you sort of take your foot off the gas pedal or you sort of say like, "Hey, this is enough"?
Mm-hmm
Even though they're not necessarily seizure-free, but you know, they're just sort of reaching that tolerability, and sort of how do you mix and match and go through that process of thinking through the different options? 'Cause as you noted, for many patients, the list sort of starts to get whittled down very quickly.
Yeah, I mean, it's an important question. You know, I talk about with patients all the time. You know, obviously the initial goal of treatment is seizure freedom and the paradigm is usually try one medication in monotherapy, try a second medication in monotherapy if the first one fails, and then proceed on to combination therapy.
At some point, I have a conversation with the patient who's still having seizures and say, "Well, you know, we have to weigh the benefits of becoming seizure-free with the risks of additional therapies or side effects." Then I start focusing my strategy on, "Well, let's work on the most disabling or the most dangerous seizure types." If I can make somebody not have tonic-clonic seizures and maybe have you know focal awareness seizures or focal impaired awareness seizures, I may not make them seizure-free and I may not get them where they wanna be in terms of being able to drive or work in the jobs they wanna work, but at least I reduce their risk of mortality and morbidity.
That's, you know, it seems like a consolation prize for patients, but, you know, after many years of struggling with medication trials, you know, I think people are willing to accept it.
Great. That's helpful. Bernard, you mentioned the hyperexcitability that you often see in between seizures. I'm just curious if you sort of have an assessment of, you know, how important is that clinically? And, you know, is that something that would be sort of just a downstream benefit of an effective medication, or is that something that you need to specifically think about?
That's what I think the way we're presenting or thinking about it as kinda leading edge of an efficacy marker, right? If you're dampening excitability, as you see on the EEG, that we would expect to then turn into seizure reduction. It may relate, and then you alluded to this, like there's shared pathophysiology, you know, that may be driving the seizures and the comorbidities. It just shows that pathophysiology is active even when seizures aren't. I would say we don't know what the clinical significance will be beyond seizures, but it should sure tell us that you're dampening excitability, you're on the right track, and would expect to have efficacy on seizures.
I mean, there is, you know, good evidence from other types of childhood epilepsies that the burden of these interictal discharges translates directly, especially during sleep, translates directly into cognition. Reducing the spikes, you know, what colloquially is called cleaning up the EEG can improve learning and school performance and attention.
Yeah. I think we have two indirect measures already of that, Doug. One by itself, if we've seen today, normal, quote-unquote, normal kids or non-seizing kids don't have them. So indirectly, you should ask, like, what's really going on here, right? The second was on the KCNT1 model that Steve showed. Those spikes are always present there. They are really not seizing. But then when you remove them, the cognition, which we are calling cognition, the nests, building behavior comes back. Once you get them back, remove the drug, they don't form nests either. It's a connection here. It's indirect evidence. It's not a direct evidence, but it's pretty strong indirect evidence right now.
Quite importantly, maybe we haven't, and I'll take a second to explain why we are doing this three-month run-in observational study for PRAX-222, prior to the PRAX-222 initiation with drug. We want to very objectively measure those things. When you go to the study, we understand on those patients instead of in the cohorts. Then we can have a conversation with the agents. They were incredibly positive on the dialogue with us. I think we hear a lot about the FDA not being positive with companies. We don't hear enough about when they are. I wanna say how pleased we are with the agency conversations we had so far in general across the board on trying to extract as much data from every patient, and that's another way that we are doing this.
We're gonna see, but we're bullish about it. Yes. I know you've been waiting for a while. Yeah, sorry for that.
It's okay. It's all good. First of all, thanks for bringing us all together. I know you could have done this virtually, but it's nice to see everybody and all of our colleagues together. Thank you for doing it. Couple questions for Bernard and a few for Dr. Friedman. Bernard, I don't know if you commented on what the age range will be for the PRAX-222 study, but it could be helpful to help us provide a range or how you get to that. Second question is there a correlation between the IED burden to seizure frequency, and what that would be? And then whether that correlation is the same when you go from the different subtypes of epilepsies. You could be using that, you know, for other studies as well.
I have one or two for Dr. Friedman.
Yeah, sure. Thanks, Ez. It's a pediatric study, so we're going two to 18, and then we hope over time we'll be able to lower the age range and get to children as soon as they start, as soon as they're diagnosed. I mentioned they have seizures within the first few days. Broad age range there, as you saw, kind of stable clinical characteristics. That works. To your second question about, is there a relationship between seizures and interictal discharges. I'm looking at my colleagues, and have we looked at that? I'm thinking.
We need to look at it in terms of the possibility of an
Yeah.
Because the seizures are self-reported, and they may not align with the EEGs. With the observation study, we'll be able to answer it in a more structured fashion.
Dr. Friedman, we as analysts try to always look at clinical studies when they get posted, and we try to figure out if there are clues in there that helps us identify that the sponsor is capturing a homogeneous population.
Mm-hmm.
Now, as you know, Praxis approach and, you know, SCN2A and SCN8A and focal epilepsy. What type of patients or inclusion/exclusion criteria could one use to really create the most homogeneous population to be tested in a clinical study? If you could just give us some
Yeah.
Notes and comments there, it could be really helpful.
I mean, I think with some of these targeted therapies, obviously having, you know, the actual monogenic disorder, and not only, you know, and perhaps, you know, not just the gene, the pathological variant, but a functional consequence. So a monogenic disorder that is a gain of function or loss of function, when you have is probably the most homogeneous population you can get. You know, we don't know what the effect of genetic background is on the severity, the expression of the disease. You know, the SCN1A story is very important.
We have people with the same gene mutation with a whole range of disease severity and phenotype, and that probably is related to the genetic background in part. I think, you know, I'm not worried about capturing a homogeneous population for the monogenic epilepsies. For common epilepsies, I think that may require some thought, and it, you know, depending on the mechanism of the drug, may require, you know, excluding certain folks. Like maybe patients with post-traumatic epilepsy may behave differently than patients with focal cortical dysplasias because of the underlying biology of their epigenetic process. That remains to be seen. All of our symptomatic therapy trials have not done that yet.
As we get more precision in our mechanism, more targeted, we may need to start to think about how to do that. I think, you know, that that's gonna require a lot of input from the community.
Yeah, I have a question. This is Eddie Hickman from Guggenheim. I have a question on these DEEs, which are obviously named because they're developmental in nature. Are there aspects of the disease or are there particular diseases that are sort of untreatable or undruggable because there are sort of permanent structural or cellular changes that happen during development, such that just changing the state of the channel or the level of the channel isn't impactful? Sort of how are you thinking about that when designing some of these rare studies?
I think for some of these disorders, if you've had a brain that's been seizing for 18 years, there might be changes that have occurred that are irreversible. The field doesn't know, and I touched on that a little bit about the things that we did see that were reversible, and it was quite remarkable how reversible they were. Some aspects of the disease will always be reversible. Correcting the genetic lesion is gonna be beneficial because that's a continual change in the function of that brain. I think it's gonna be that we'll see over time. We know in some cases, it's not common that in the KCNT1 cases, some of the children get microcephaly.
Mm-hmm.
That's not a common finding, and there's a whole group of children that we think, you know, that have normal brains and that goes on. We're not seeing those signs. In PCDH19, which is you think would have some structural elements to it because it's a cell-to-cell contact disorder, when you look with MRI, there are no structural changes in those brains. I think we're not seeing in general with DEEs wholesale morphological change, which is a really good sign of a irreversible developmental issue. I think we're quite, I'm quietly confident that that's gonna something we're gonna be able to contain. The early evidence is very positive as well.
Yeah.
Maybe even more importance there, and without giving too much on the tips on things we're working on, is there are changes that happen within the channel, like migration or density of channels on different types or place in the neuron, like when you're talking about like NaV1.2, NaV1.6 for the sodium, or when you're talking about interneurons that don't get retained or retained throughout the development. So we touch a little bit on the surface today, but when you look into this disease, we're looking a lot deeper in terms of, is this gonna work at the two-month-olds, and is this gonna work on the five-year-olds equally? Maybe that's not as explored as it should, but it's something we take incredibly seriously once we're declaring candidates.
This reversibility question, it's always a question until you have a therapeutic, but it's also one of the nice things about having a broad age range. Like we said, you do get a sense of, is there a window? Do we need to go earlier? That helps us make the case for if we need to go earlier. I think to be determined, but the logic is as Steve laid out.
Gotcha. Just a quick follow-up on the sort of seizure freedom conversation we've been having for Dr. Friedman. Now that there is a drug out there that sort of is pretty good about doing that, with cenobamate, is the clinical bar sort of changing with your colleagues that like that is becoming important when you're looking at these novel therapies? Given that that's not the registrational endpoint for these studies, like is that something that you're thinking about in trial design that like those would be important endpoints to look at because that's where the field is going now that there is a drug?
I mean, I think it's gonna be an important endpoint for the market, right? You know, we're still doing placebo-controlled trials where the outcome is percent seizure reduction for registration of common anti-seizure medications. I think, you know, most companies are including significant amount of seizure reduction or seizure freedom as an early signal to whether or not to pursue you know, later-stage clinical development because, I think, you know, they wanna differentiate themselves from the 18 other drugs, and that right now seems to be the best way to do it, better efficacy. It could be one of, you know, the other aspects that we discussed.
I think it should be, you know, part of early clinical development is really to shoot for, you know, an improved efficacy over existing therapy. Unfortunately, you don't know that until you get that into, you know, at least phase two trials with lots of people.
Yeah.
Thanks. Ritu again. Dr. Friedman, as you think about the pathology of many of these epilepsies, how do you tease apart some of the clinical dysfunction, and the sort of the known defects for those diseases where there are known defects, right?
Mm-hmm.
How much of the dysfunction is sort of upstream of the seizure, and how much is downstream of the seizure? You know, as we think about these symptomatologies, I'm wondering like what can be decoupled from seizure reduction and what may not be.
I mean, I think it's a good question, and it probably varies a lot by the DEE. Whereas some of them, you know, there is, you know, the major impact of the developmental trajectory is the seizure burden. If, you know, if you could stop seizures early, then you may have a normal developmental trajectory. Infantile spasms, you know, is maybe one example where there's, you know, good evidence that early aggressive therapy can, in many cases, improve developmental trajectories. You know, it's also a heterogeneous disorder.
I think for a lot of these, especially disorders of the synapse, they're, you know, some of those comorbidities are related to, you know, other things that the synapse does. You know, the comorbid autism and other cognitive dysfunction probably, you know, has less influence from the seizures.
That's super helpful. Just back to the PRAX-222 conversations with the FDA. In how you see that integrated trial design right now, you'd mentioned at some point you were gonna start looking at optimized dosing.
Mm-hmm.
Sort of more spread out dosing. That wasn't gonna be in that initial-
Correct.
Dose escalation part, right? It was gonna be after. Do you see that as like maybe post-registration, or is that something that you plan on having before any potential filing?
We're likely to have some of that information before filing 'cause some children will complete the randomized blinded period as we've proposed it. We're just talking about what we proposed. They'll complete that, and then they would roll into the longer-term extension where we have less frequent dosing. Well, yeah. Yeah.
Okay. Got it. Thanks.
Thank you. Laura Chico, Wedbush Securities. Just one last one for Dr. Friedman. Could you talk about how genetic screening has changed in your practice? Maybe not just the pediatric setting. I think you still treat patients into early adulthood, so
I treat teens and adults.
Okay.
Actually, this is the point I really wanted to make here, that you know, these are not disorders that present in childhood, but if the children survive their epilepsy, they will become adults. You know, while most of our efforts for screening, for instance, a lot of the sort of sponsored screening, subsidized genetic testing that many companies, I think including Praxis
Mm-hmm.
support and insurers, you know, is focused on children. We have a huge population of adults, which we used to put in a bucket called symptomatic generalized epilepsies, that have never had genetic testing. It's, you know, still takes effort now to get it covered by insurance. It's something that I do as part of my practice when I can. When I see patients with undiagnosed childhood onset, infantile onset epilepsies and intellectual disability, I will try to initiate a genetic workup because the same therapies that you know that are being developed for children will one day be available to these patients if we have a molecular diagnosis for them.
For that case study you provided, in that type of scenario where you have somebody presenting in adulthood, how often are you screening those candidates?
For most of the, you know, common epilepsies, why I don't, and because the yield is very low. Most of our screening looks at sort of monogenic pathogenic variants. Whereas probably in the adults with common epilepsy, they have polygenic risks of more common variants, that's attributed to more common variants, and that's just not part of the diagnostic. Are we recording yet? I screen them when they have childhood onset epilepsy with intellectual disability. I screen them if they have a family history of epilepsy. Those are the main populations.
Yeah. Miles from William Blair again. You presented some pretty interesting data on the number of like medications that are used in these patients. Seems to be a lot, and I'm particularly interested if you do get PRAX-222 to lower, you know, to 35% knockdown and you're on background like sodium channel blockers, how are you gonna control for that use? Like, if that pushes you further down the functional knockdown sort of threshold. Especially if you start controlling for that use, what happens to the other eight anti-seizure medications that these patients are on? I mean, is that a problem that you see in the clinic, Dr. Friedman, and are you concerned about that? I'd love to hear comments from both the company and you.
I mean, you know, from a practical standpoint, we use medications with overlapping mechanisms all the time. You know, and sometimes it works, and they work in combination, but not alone. Two sodium channel blockers. I think that, you know, I don't think that sort of two therapies targeting the same mechanism would present a, you know, problem for me in terms of interpreting the data as, you know, as long as the groups are balanced in terms of overall types of agents used.
Obviously, that it'd be a great problem to have, right? You know, what the one way it could play out is that an ASO like PRAX-222 is kind of the basal therapy. You've reduced levels of the channel. Maybe you still need to modulate the channel on top of that a little bit. You know, our hope would be that it could be a monotherapy, but maybe you have lower levels. The way you can of anti-seizure medications. The way you run a clinical study is people come in on whatever they're in. They're obviously gonna be taking a number of different medications. Then you have PRAX-222 will be added in a blinded fashion. You'd like to keep things stable and only reduce them.
Ritu asked about that, you know, open label extension, the third part of the study. That would be the place where you start to ask if they're doing really well. Do they need all these, you know, toxic sodium channel blockers? I think we've thought about this a lot. You just wanna go about systematically so that, you know, Dan and colleagues have the data they need to interpret it, and you don't have too many moving pieces unnecessarily.
I'll connect this back to our first question, Myles, as well, right? You could imagine with Delta again. Once again, giving too much that knowing that the channel is blocked, right? We know sodium channel blockers do a pretty good job blocking the channel, maybe too good of a job, and then you can't do anything else there. We just have naturally a safety valve. To your question about the. Is the drug in the brain? Is that doing what's expected? If you hit toxicity, for example, you know what's happening there. Now we can start working with the baseline therapy because you know the additive therapy PRAX-222 or any other that we might be developing is present and is doing what's expected, which other drugs didn't have the benefits. Other ASOs didn't have the benefits of doing that.
We see actually as a potential feature that we can play with, and more to come on that. Safety was the number one thing we built into this investigation by far. Maybe why it's being relatively simple, the dialogue. You're gonna see we incorporated some of those things in the design. Okay. All right. It seems like that was it for questions. Thank you everyone again here in the webcast. Appreciate the time and more on the next analyst day in a couple of months. Thank you.
Thanks, man.