Good morning, everyone. It's a real pleasure to be here with all of you. The government is up, so we don't have to worry about that. So we can focus on our update for the R&D day at Praxis. It's incredibly humbling to be here with some of the updates we're gonna be showing today. Before I get started, just want to make sure we're gonna be making forward-looking statements, refer to our SEC website for some of them. Together with myself, we're gonna be joined by some of our senior colleagues at Praxis, but also by Dr. Espay, an expert in movement disorders, by Dr. French, that requires no introduction, an expert on the epilepsy field as well. The format of the meeting is gonna be focused on some of the key topics that are relevant for us right now as a company, and shortly thereafter, for each one of the sections, we're gonna have a Q&A. I more than encourage, I ask you to participate during the Q&A session. I think we can have a very robust discussion with our experts here during all of that. Just a reminder, and I know most of you, either here in person on a beautiful day in New York City or in the webcast, are quite familiar with Praxis, but we do have two platforms. One is small molecule platform and one oligonucleotide platform. We're very excited about both of them. I'm gonna be giving updates today on both sides of this equation. But one point that I wanted to make, upfront is that all of that is enabled by our understanding of genetics in the brain, right? So how genetics manifests and how the lab creates, unfortunately, certain conditions that affect patients, leading to CNS disorders. Now, specifically, for the time we have today allocated, and for the time of the year, we're gonna be focusing on three major programs. Alex is gonna discuss ulixacaltamide, our late-stage program in phase III for essential tremor. The main areas we're gonna be covering there is the confidence we got from Essential1 after the initial analysis and beyond that, to enable our phase III program. And then the second is: how is that phase III program? I know many of the questions we got throughout the last several months from all of you is how we're gonna operationalize, what is the power of that study? Like, how the recruitment and so on. I think we have some quite exciting news there, as well. Karl is gonna be reviewing the 628 program as well, something we are incredibly excited about, like, which in our view, it is really the ultimate way to disrupt, positively, focal epilepsy and generalized epilepsy in the markets, which is very much needed as we're gonna continue to discuss, on the next, few hours. And lastly, I'm gonna discuss a little bit PRAX- 222, and what we've been doing about it and what we've been seeing, with these patients. I believe it's gonna be quite exciting. I hope you are as excited as I am at the end of that conversation. Just going back to the principles here, and Steve is gonna go in a lot more detail about this, but I want to remind us all, right, on how we look into drug discovery, drug developments, de-risking as a framework for Praxis. So look into genetics as, like, a foundation. You might be aware of that, but drugs with an understanding of the underpinnings from genetic perspective are twice as successful at the end when you look into all the analogs for the ones that are not. So we see this not only as an engine, but as a de-risking factor for us as well. The use of translational tools are gonna be quite obvious throughout the presentation. Obviously, every single company doing drug development use translational tools, but we're looking here into very specific ways to enable the program, understanding the biology, and measuring what matter, and using that measure to answer the question that we are primarily asking. Efficiency and rigor or speeds and quality are not trade-offs. You can do both when you're very deliberate about doing both, and that's where something we're incredibly committed about doing, and that's gonna be incredibly clear when Alex described the Essential 3 program, that is how we're calling our phase III program for ulixacaltamide, on how we are bringing that to life, as we speak. It goes without saying, and it's oftentimes more rhetorical than true when people say they are patient-centered, patient-guided, but for us, it's very real. From the very beginning, when you look into genetics or population genetics or specific, for what kind of translation does that matter for patients? Is the way we are delivering the clinical, drug, the clinical trial, are we meeting the patients where they are? Is something incredibly important. Do we actually understand what are the needs? And that's gonna become quite obvious in some of the areas, both in essential tremor and epilepsy. They're gonna go there. For fundamentally, this audience, right? This is a value conversation. And we need to make sure we understand as a company, and we give you the confidence as our shareholders and investors and others, that we understand the value on both sides of this equation, both on movement disorders and on epilepsy. It's gonna be quite obvious at the end, at least it's obvious for us, please criticize us if that's not the case, that the value is tremendous on both sides of that. Just want to illustrate by going through a very high-level idea of value for, first, essential tremor and then the epilepsies that we're going after. When you look into essential tremor in the United States alone, arguably someone in this room has it. 7 million individuals outside of the door are now coping with it. It is not a benign condition, as being described before. It affects every aspect of their lives, and it progresses at the patient's age, right? In most cases, not in all cases, but in most cases. About 2 million of those patients are seeking treatments, to some extent in despair, as Alex is gonna go through the funnel here and understandings like what happens when you get through a treatment, what happens on the next month, what happens on the next year. And unfortunately, it's not a beautiful picture here. So from an unmet need perspective, it's undeniable that it needs to be disrupted, and it will be disrupted with ulixacaltamide. From a value perspective, it's a wide-open market. When you compare to even less common drugs, like, it's abysmal, the difference between alternatives patients have, and every disease, in my view, is important, right? So I'm not making here a relative importance on where drugs should be developed for A or for B indications. That's not by no-- by no means what the chart is meant to show, but it's really the inability to address this disease with what we have right now. So one has to ask why in a situation like this. And the why is a heterogeneous disease, endpoints that have not been defined, understandings of the biology and fundamentally a mechanism that address fundamentally the dysfunction in the brain, the oscillatory networks that are not behaving the way one would like them to do. And the collection of all of that is what we are trying to address today with ulixacaltamide. And by the end of the conversation, I trust that all of us are gonna be on the same page, how that's gonna happen. I also hope that I was here today, and I know hope is not a strategy, and I always use that, but I do hope that we were here today saying, "Oh, but in epilepsy is completely different, right? We know how to treat epilepsy for decades and decades, so therefore, the picture is different." But the picture is not that different. Most of the discussion in the field right now is about the middle of this chart. It's about the patients with refractory seizures. And yes, if you look into that alone, and there are 1 million patients in the United States that start a treatment, stop, don't control their seizures, cannot drive, cannot care for their families, cannot be in a hotel room alone. Those are implications of having one seizure, not many, one, they cannot control with everything because the because here is gonna be explained later, right? It's not only the efficacy, that is the tolerability, that plays a huge role here. That alone would be a massive market. But I'm gonna invite you to think about what's happening with the other 2.5 million patients today as well. Because they're by no means, like, enjoying what's happening and just, like, living their lives as most of us here are, without the constant fear that they're gonna have a breakthrough seizure. Or with the constant fear or that the side effects are too much for their life, and they might need to trade off, like having a seizure for continue having a side effect. So that's quite important. But to also know, we do have a smaller indication, and smaller is always relative, in terms of the GEs that we are aiming to resolve. When you look into that market, and while there are fantastic advances there, like looking to the left-hand side, and I, I'm very thankful for the scientists, for the companies, for people in the fields actually driving, like, great solutions for SCN1A patients or Dravet syndrome patients for Lennox-Gastaut patients. Is there still residual needs there? Absolutely. And, and I'm glad there's many, many companies working on that, and it's wonderful for, for the fields. But when you look into the right-hand side there, like if you start walking from that first bar, the needs for patients with other GEs, and we created subset here on things that we are actively working to address, are incredible. The difference is that there is nothing for them right now. So when a patient with SCN2A, gain of function or loss of function, but let's focus for a second on the gain of function here, exhausts all the anti-seizure medications as they happen very quickly, they are at the mercy of the next seizure. And, and that's quite important, right? Because think about your own life and, and the loved ones, and having that next seizure, how important it is. So I'm gonna take that opportunity and to some extent, the hope there, to talk a little bit about the 222 program, because we haven't really explored to its depth, how excited we are about it. So as you know, PRAX-222, or now we have the proposed INN there, so we can give it a name, and hopefully soon a last name. The aim is to revolutionize the way ASOs are developed for epilepsies. That was the aim from the beginning, when Dr. Petrou and Alex, Kelly started working on this as a very small group of people trying to solve this problem, right? But it is still the aim today that we are really working very hard to disrupt. Maybe just to ground everyone on SCN2A. When you look into the condition, right, patients with mutations on the gene that encodes SCN2A, NaV1.2, this sodium channel, in the brain, or SCN2A, they have a very predictable, to some extent, life. They seize at birth or no later than three months of life. And I know many people in this audience here and the webcast have kids. So just imagine that for a second, right? A newborn, and seizing at that day, they don't go away. There are many other conditions that kids have seizures at birth, and I don't wish any of them to actually ever happen, but that you can control pretty well, but you cannot. They are refractory, and they continue throughout the life of those patients, right? The one concept that might have been lost is that there is a direct correlation between Sudden and Unexpected Death in Epilepsy with the number, frequency, and severity of seizures a patient have. So when you're talking about reducing that, we are talking about survival, right? We're directly linking not only quality of life, as many talk, not only the reduction in an endpoint, but really keeping these kids alive for better medical events, better treatments, better understanding of how to give those treatments, or simply to enjoy more time with their families. So our mission is really to change the trajectory, like, one patient at a time. We always said that, right? A lot of you been interacting with us a very long time, but this came to life, several months ago, like about seven months ago, in a way that was unexpected for us, and that's how I would like to start this conversation. We got a call from a team saying, "We have a patient here with us, and this patient was born in convulsive status epilepticus. We tried to do everything we could to rescue." Where a lot of you know, like other companies are working on that space as well, they couldn't do anything. So we know the trajectory, right? They're gonna continuously seize, have convulsive seizures, and unfortunately, perish at the most part. And the question at that point in time is: would you be willing to provide PRAX-222 on an emergency basis? Now, put ourselves in our shoes at that point in time, right? This would be the first patient ever to receive the drug. It's an emergency case, and as you can see here, it was not only that, he was a preterm newborn. So we go back to the framework. Are we here to help, or are we here to just, like, play into the developments the way we normally planned? And I think the decision at the end of the day was that we're here to help. Obviously, we had multiple meetings with the team there, a fantastic team of physicians, and parents that were engaged on this. The expectation at that point in time is, well, maybe you can help them get a little bit more rescue medications going on and a few other things, to keep this kid stable. But what we actually seen was fairly dramatic. So what we're seeing in this patient is after one dose, the very first dose, within the very first month, he went from continuous convulsive seizures. We're talking about an EEG that does not change patterns here. So I wanna be clear, right? This is not like you are five minutes, and then it goes away, and then five minutes and go away, as sometimes status epilepticus is. This is a very, very severe case on the ICU, without really any other. And what you're seeing is periods that was not happening. So encouraging, but not necessarily the end of it. Now, you fast-forward to seven dose of the drug. And remember, seven dose is not like seven days. Seven dose are seven months or more here, right? We're talking about twice as long of a period of observation for every anti-seizure medication that has been approved in the United States to date on their pivotal trial. I wanna put that in context, right? The way to approve drugs is 12 weeks observation versus the 28 days before at baseline. Just to create the framework that it goes beyond the normal period of observation for the first studies they were looking in. And as you can see here, and I'm not read all of this for you, it's dramatic, the change. No status, basically no seizures. And what for me was quite phenomenal was shared by the clinical team, is like, being able to breastfeed, right? That is a very high function, requires a lot of coordination, requires a lot of, like, other things going on in the environment for a patient like that. The patient is clinically stable. The actual seventh dose was just delivered, like, days ago. So really doing great. Now, if I show you data from one patient, you'll say: "No, Marcio, this is great, and I think we're all excited about it, and I'm glad you're helping one patient." So our next question is, what is happening within our actual trial in the United States, where we've been running a study in the United States, as you are all aware, which we're calling EMBRAVE? Just to bring it back to what we aim to do in EMBRAVE, in the current study here in the U.S. So we're looking for primarily safety, right? That was the objective. So got to the end of EMBRAVE, gave them four dose, the patients were safe, like, no major issues, no major, like, side effects, would say success. That, that was a success. Now, because we care a lot, our bar was, we expect to see something going on as well, on their seizures, on in overall. Patients were dosed every month, and then they collected daily seizure information, and then the following month, and so on. So at this point in time, as we stand here with you today, we have three of those completed, three months observation. So three dose, plus two weeks after for the observations completed for all those patients. The fourth period is forthcoming in the next few weeks, as well. And what we're seeing, I believe, shocked us to some extent. Not because we're not expecting, but because we're incredibly happy with what we are seeing. As some of you research, talk to opinion leaders, wrote in your reports on the analyst community here, on the ones, investors on the phone that talked with us. If you've seen 10%-15% seizure reduction on this cohort, we should be really, really happy, right? Because all those patients are on best standard of care. Like, everything was tried, they're stable on that dose, there's nothing else to be gained from the treatment they're in. But what we actually seeing is much better results than that, at this point in time. So you see here, after one dose, two dose, three dose, apart, we're seeing orders of magnitudes than our expectation. And as you can see on the range, on the bottom here of the slides, of course, there's variability within those patients, but every one of them benefited. So when you put this together on four patients here, the patient on the emergence access, it becomes very, very hard, no matter how much you want, to maybe add some caveats, to not believe that this is the most incredible results that's been seen in this disease ever, right? It would be great to just stop here, right? But one of the things we heard again and again from key opinion leaders in this field is, did it reduce just the number of seizures, or there is any other measure associated with that, that might be important for the patients, for their lives? As you all know, there is a big, like, agenda push, rightly so, by the FDA on understanding how does that impact patients' lives at the end. And then when you look into the number of days in the month that they did not seize at all, right? So zero seizures entering that day. See the baseline there, 21% on that first month, and then in general, it's almost double, right? So from 21% to 33% number of days is a very, very significant. So I'm gonna ask you, once again, to ask yourself, you have a kid with this condition, 24-hour care, what happens when they are actually not seizing that day? To your life, to your quality of life, to the interventions, and everything else. Now, there are much more to come as we continue to advance this, but it's quite incredible and unprecedented. It's also timely to some extent, as we're preparing for this conversation the last few days, and I got a text on Saturday saying one more patient died in the United States, 10-year-olds with this condition. That hurts, because our speed is never as fast as the families expect us to be, as these patients need it to be, but it creates an extra motivation for me at least, and for all of us at Praxis, to actually move this, to actually help these patients more and more. Now, none of this would matter if the drug was incredibly toxic and we couldn't give this to patients, or have all sort of weird side effects, but that's not the case. We had no treatment-emergent adverse events or they are related to drug or serious adverse events related to drug. Not showing all the lab values and things like this here, and we're gonna do this in a later date, but I can tell you that it's pretty uneventful as well, boring, as safety should always be, for situations like this. So incredibly excited, but it does change the trajectory of the program for us because our target profile was less than what we are seeing with this cohorts right now. So there are very rare times in history of drug developments that one can reach the target profile in the first cohorts. So our proposal for next steps here is, obviously, we're gonna wrap it up, the collection. We want to make sure that we do that, compile this package on the next several weeks. Have an interaction with the FDA, which we obviously expect them to be very open to the benefit-risk that exists here for a disease without any other treatments. There's not only any other treatment available, there's any other treatments in development. There's absolutely nothing else in the clinic for these patients, so therefore, the urgency, as well. Having now decided that this dose is efficacious to expand this cohort and to run a pivotal trial. Actually, now that I said the dose, I was remiss to actually reflect on that dose. You're all very familiar with intrathecally delivered ASOs, and with the great benefits that are being seen, with some of the setbacks that happen in the field as well. And if there is one thing we know about drug development in general, is like you should always try to give the least amount of drug that's gonna give you the maximum benefits, right? Not only because it's nice, but because drugs do other things when you give a lot of them, chemically or biophysically or biochemically, they just happen. And this ASO we knew from the very beginning is incredibly potent, distributes really well on the brain, and it's giving a 1 mg dose every month. So very, very happy with where we're here. Incredibly humbled by where we stand as well. The study in the U.S. by design was done with Dr. James Wheless in Tennessee. So I would be remiss not to actually thank him and his team, who are like world leaders in this kind of study. They really jumped in, brought all the patients there, did the best possible care these patients could have. But ultimately, the heroes here are those patients, right? That when they got to the trial, despite not having other alternative, they didn't know the risk they were putting their kids in. So I just want to take this moment as well to thank them. It brings me to our, like, motto, tagline, philosophy for life at Praxis, we always say, "We're there for more." And we're there for more for each one of those patients, for every execution, for every study we conducted, for every patient and life we touch, for every conversation we follow through. I'm sure you all relates to that. And this is a very clear example of what there for more actually means for these patients. So I sincerely hope that you all excited as I am, as everyone else at Praxis and obviously, the community, at large out there is for this drug to move forward. So before I move to Alex to give us an update on ulixacaltamide, Karl might. I just want to review very quickly and go back to the calendar for the milestones for us here. As you can see, I'm gonna focus on the right part. So we're gonna be discussing the ulixacaltamide phase III program, two studies, as Alex is gonna review. Initiation Q4, then we're in Q4. Hard to believe we are here already, but we're starting there. We're gonna be fast and furious about driving that study to completion, as is gonna be clear by the end of this conversation. Karl is gonna discuss the readouts, expected readouts by the end of the year for our PPR study with 628, and why we are doing it, why we believe that's an important additional piece of information. We just talked about EMBRAVE in general, then there are many other things. The one change that I wanted to highlight here is, while we have very good interests and patients for the 562 study, we underestimated the fragility of these patients during the enrollment periods and really the ability to get to these patients on the time that we had. So we're extending the time to complete the enrollment for that study a little longer, mostly to allow for this entire screening process and the stabilization process, actually, for the counting of the seizures and make sure these patients are there. We also pivots to a hybrid study design for 562, where one of the biggest issues that we're facing and others are facing this is that patients wants to participate in the trial. They are willing, they but they can't go to the sites because there, there's really a lot when they move. So we created a hybrid network where the healthcare team goes to their house and do the assessment versus the other way around, which is, to our knowledge, being discussed for a lot in epilepsy, but has not been implemented. We're very happy with the implementation, with the quality of it, and using the learnings for future studies as well. Before further ado, I'm gonna ask Alex Lacroix, our head of movement disorders, to talk a little bit about the essential program. Thank you. Thank you, Marcio. So as Marcio mentioned, my name is Alex Lacroix. I'm the program lead for ulixacaltamide at Praxis. So two things. So there are two topics on the slide. The first, I just want to emphasize, is not a clinical update on ulixacaltamide, but really, how are we leveraging the insights from the Essential1 program into our phase III program. And as Marcio mentioned, the phase III program is Essential3. Before I get started, I just want to point out, I work with an exceptional group of people at Praxis. Whether it's the study teams that are supporting the program or the broader network of staff that are supporting those teams, and even our leadership team, which is highly engaged in the program, and as Marcio said, is daring the team to do more as well. I just wanna recognize that all of the data you're going to see is really reflective of that team's efforts over the past seven months since we released top-line data. Essential tremor is an underappreciated disorder, and as Marcio mentioned, it's often referred to as a benign disease, a benign tremor. I would ask the question of benign compared to what? Like, vanilla ice cream is benign, right? Like, but a disease, no matter what the disease, is not benign. If you were to ask any patient with essential tremor or the family members that support those patients, essential tremor is not benign. And it's really surprising that there's that perspective of this disease, because essential tremor is the largest movement disorders in the space. There are approximately 7 million patients with the disease. And their daily activities are severely affected, and because they're affected, these patients also acquire comorbid conditions around anxiety, frustration, depression, things that not only impact them and their family members, but also are triggers for the disease as well. One of the reasons why there's a misperception around essential tremor is a perception that the modalities for essential tremor are viable for these patients. There's an approved therapy. Propranolol was approved back in 1986, but the vast majority of patients cannot take propranolol because it is contraindicated due to health conditions, health risks, other medications they're taking as well. Based on our claims data, we know that the small fraction of patients who actually take propranolol rapidly discontinue. A small number start taking propranolol, an even smaller fraction of the patients who seek treatment end up maintaining propranolol therapy after two years, 20%. As Marcio has mentioned, our goal is to disrupt care in essential tremor. We intend to be not only the first in class, but the best in class, novel modality in essential tremor. We are, based on our emerging profile with Essential1, going to be significantly differentiated in terms of efficacy, clinically meaningful benefit to patients, safety and tolerability, adherence, and it will be able to be used in a broad section of the patient population, not a subset like propranolol is. We'll also share some early data that shows that it can be used even in that subset of patients that are on propranolol, with or without having incremental benefit. Essential tremor, or, I'm sorry, Essential1 has demonstrated clinical benefit at multiple time points in the study, and I'll share that with you. But even in the first eight weeks of the study, the efficacy has been compelling. We'll show more data that shows that it's only its long-term benefit and durable, and also is confirmed in patients that are switched from placebo, and also has a well-tolerated safety profile as well. One of the other things that we did in Essential1 was deliberately tested concepts and operational strategies that we intend to implement in our phase III program as well. An important aspect of this is that we were able to have a data-driven discussion with the FDA in our end-of-phase II meeting. So where they agreed to mADL11 as our primary endpoint, a study duration of 12 weeks and other design elements with the study as well. Another operational consideration here is that we're going to be taking our robust patient recruitment strategy, which I'll talk about more later in the slide presentation, and applying that to our phase III program to rapidly enroll this phase III study. So So I'm sure everybody's aware of the Essential1 study schema, but I just want to point out three things, 'cause there are 3 main takeaways with the Essential1 study. So we saw in the first part, through week eight, we saw proof of concept, clinical proof of concept with Essential1, with the ulixacaltamide. In the second portion, in the double-blind lead-in, which I just want to remind folks, is when we took all of the placebo patients and transitioned them on to drug in a blinded fashion, patients did not know if they were on active or placebo going into that study. We saw two things in that period. One was a durable effect, and the second was a confirmation of drug effect in the placebo patients transition to ulixa. Then the third part of the study, in our crossover design, we confirmed drug effect with a randomized withdrawal. I'll walk through the data and in subsequent slides. So again, FDA has agreed to mADL 11 as our primary endpoint in the phase III program. When we look at the Essential1 data through that lens, in 116 patients, which was the study population in Essential1, we see statistically significant results and separation between placebo and ulixacaltamide patients. When we look at two clinical outcome measures, one is a patient-reported outcome, and the other is a clinician outcome measure. PGIC is a patient-reported outcome, that is the patient's perception of whether their condition is improving or worsening, right? When we look at that data and compare it to placebo, again, we see a nominal value in that group. When we look at the clinician perspective using CGI-S, which is a severity scale, again, the clinician's perception of whether a patient's disease is actually becoming less severe or more severe. Again, a p- value that is significant as well. So we now have 3 data points, mADL11 and two clinical outcome measures that all point in the same direction. So it's a reasonable question to ask, is mADL11 a clinically meaningful measure? What is clinically meaningful about a point improvement, 2-point improvement, 3-point improvement in mADL11? So shortly after we had our top- line results back in March, FDA came out with guidance about how to use these clinical outcome assessments, like PGI and CGI, and correlate them to a clinical measure like mADL11. And we applied their methodology to this analysis, and found that a 2-point improvement in mADL11 was clinically meaningful, and that is our minimum clinically important difference, right? So when we look at our data through that, through that lens and actually setting a slightly higher bar, not 2 points, but a 3-point improvement in mADL 11. Again, at eight weeks of therapy, we see a clear separation between placebo and ulixacaltamide groups, statistically significant results. And one thing I want to point out, again, this is not a mean three-point change. It's not a mean 3-point change. It is patients, the proportion of patients who met that threshold, and almost 60% of patients on ulixacaltamide responded in that, with that, met that minimum 3-point change. And I just wanna put it in context as well, that it's a minimum of 3 points, and at the upper end, it was a 17-point change in mADL 11. So pretty significant effect. And when we go out to week 14, two. There are two conclusions that we can draw from that. The first is that the patients who are on ulixacaltamide throughout the study continued to improve, and it was 55%, at week eight, and 64% at week 14. So a continued improvement in that group overall, and more importantly, is that we see a confirmation of drug effect. So when the patients who were previously on placebo at week eight are put on drug, we see a comparable effect, a rapid on effect in the patients who were transitioned to ulixacaltamide. And again, this was a blinded period in the study where patients didn't know if they were coming into that period on active drug or on placebo. And a slightly different way to look at this is when we take the subset of patients who were on a stable dose of propranolol. There were patients that were on placebo and propranolol in gray, and you have patients on propranolol and ulixacaltamide in blue, and you see a nice separation and what seems to be a clear drug, incremental drug effect when you layer on propranolol. What we haven't included here is also an analysis going out to week 14, where we see those placebo patients who, again, 25% of the patients, met that 3-point threshold. Placebo patients, met that 3-point threshold. At 14 weeks, they look just like the ulixacaltamide patients on this figure. So a nice confirmation of effect. So moving away from a discrete time point and looking at the continuous variable from week eight to week 14, again, when patients who have been on ulixacaltamide throughout the study and looking at their continued improvement beyond the primary period of the study in the double-blind lead-in, we see almost 2 points additional improvement through week 14. And again, a confirmation of drug effect in the placebo patients who were transitioned at week eight and have a rapid response to ulixacaltamide, and again, look very similar to the patients who were on ulixacaltamide throughout the study. Almost over a 3-point change in that group as well. So all of the data that you've seen to this point is patients going on to ulixacaltamide. In our randomized withdrawal study, our crossover design study, where we randomized patients to—who were on a stable dose of ulixacaltamide—to either placebo or ulixa. And the patients who we withdrew drug had the exact opposite effect. Instead of a rapid on, when they go on ulixacaltamide, they had a rapid off, and you can see the dramatic difference between the placebo and treated groups. So one thing I want to point out is, again, like, going into the phase III study, it is not one data point that we are hanging our hat on. It is multiple data points over multiple time periods across multiple treatment groups. It's an orthogonal analysis that is supporting our phase III strategy. So and again, in multiple different ways, mADL is confirmed as a viable phase primary endpoint in our study, and we've also demonstrated what is clinically meaningful, what is a clinically meaningful level of response with mADL11, and also testing various elements of our phase III strategy as well. So just wanna again point out seven months. It's been seven months since we released our top-line results. And in that time, we requested our end-of-phase II meeting, put together a briefing book, had a very successful meeting with the agency, where we aligned, and not just on the primary endpoint, but the duration of study and dose. And also shared preliminary concepts around the phase III protocol. Coming out of the end of phase II meeting, we quickly finalized those protocols, shared them with the agency, and received feedback at the end of September. In parallel, the study team has been working on start-up activities and also doing pre-engagement with the patient community around interest in the study, which I'll talk about more in just a moment. We are poised to expand our recruitment efforts and initiate the study later this quarter. Again, seven months, this team has done that. Again, an exceptional team of folks has supported this. Our phase III strategy consists of two primary studies, a parallel design, where we'll compare 60 mg of ulixacaltamide to placebo, and a randomized withdrawal study, as well, where patients will be treated for a period of eight weeks. Patients who meet a pre-specified responder criteria will be randomized to either placebo or ulixa and evaluated over a four-week period. I'll talk a little bit more about that design in just a moment. Now, for those paying attention, you can see an innovative phase III program in the title, and that, that isn't particularly innovative in and of itself, right? I mean, we've done a parallel design study with Essential 1. This will be the third time we've done a randomized withdrawal study with ulixa. So again, these, the structure and design of these studies is largely de-risked, almost wholly de-risked, I would say. But there are two studies, and in a traditional phase III development, two studies means two protocols, two IRB reviews, two eligibility committee reviews, two of everything, two recruitment pathways. What we're proposing to do is have these under a single protocol, have single recruitment, have a single eligibility committee review, single screening, and patients that meet the eligibility after screening will be blind randomization into one of the studies. So it'll be a single pathway. The benefit is that we are looking at the same profile of patient in both studies, but evaluating them in two different ways. And one of the benefits of this approach is it reduces study bias. A randomized withdrawal study, again, patients know they're going on active drug. With this, we're actually reducing that bias, randomizing the patients in a blinded fashion so that nobody knows which study they're on. All patients that complete the study will have the option to roll into our long-term safety study as well. So a little bit more detail on the study design, clicking into it one level down. We anticipate enrolling a total of 600 patients into the study across the two sub-studies. So the parallel design study, we'll enroll 400 patients. The endpoint that we'll look at is mADL11 change from baseline out to week 12, and it's powered, 90% powered to detect difference. The randomized withdrawal study, we anticipate enrolling 200 patients. And again, I mentioned it will go out to, the patients will be treated for eight weeks. A subset of those 200 patients will go through a responder analysis, and those patients who meet that threshold will be randomized into the randomized withdrawal study. The endpoint there is a little different. It's basically taking the week eight baseline and determining response at that eight-week baseline and looking at the patients who go into the randomized withdrawal and comparing the response rates after they go into the randomized group. It is also powered to 90%. So one of the key learnings in Essential 1 was that we need to prospectively stratify the patient population. We've talked a lot about intention tremor patients as a bit of a confounder in the Essential 1 study from a placebo standpoint. We will be prospectively stratifying that patient population because we do recognize that the intention tremor population, as long as it's ET plus intention tremor, is a part of this disorder, and we need to understand it clinically. So we'll be ensuring that we are balancing that patient population across the three arms of the study effectively, and also prospectively stratifying around ET family history and propranolol use as well. And we'll be looking at, among other things, in the secondaries, TETRAS ADL and the clinical outcome assessments, CGI, PGI-S, and PGIC. So another innovation to our study design is we'll be deploying a completely decentralized study. As Marcio mentioned, we're doing a hybrid approach on the epilepsy side. This will be completely done in the patient's home. As he mentioned in the introduction, we want to bring the study to where the patients are, right? And the design of Essential3 is suitable to being more flexible in that regard. mADL11 can be done virtually. All aspects of this study can be done virtually, beginning with a structured video that will be a neurologic exam that will be read by the investigator and then also confirmed by the eligibility committee review. And then all assessments will be done in the home as well. There will be a high touch of healthcare professional contact with these patients, either through home health visits with home health nurses or with investigators via telehealth visits as well. One of the additional benefits of this, having a decentralized platform to gather data, is that the data capture will be real- time. Again, in a traditional study, oftentimes a site, a patient goes into a site, gets their exam done or monitored, and there's a piece of paper that just sits off to the side, and it may or may not get entered in, into the system right away, or it might get entered, and there'll be queries that will go on for weeks with a site. This will enable us to do real-time data capture and do quality checks in real- time as well, which will simplify the process as well. In order to maintain consistency across the study, we're going to have a nationwide network of investigators that will be trained on the protocol and evaluate patients in a standardized way in terms of the assessments and outcomes. Again, minimizing the variability across sites that we saw in Essential 1. So again, we are bringing the trial to where the patients are, and what you see on the left-hand side of the slide is our social media campaign that, when launched, will be the starting point for patients to opt into the study. And again, it is a single recruitment portal where patients will regardless go into one evaluation and be randomized to one of the two studies in a blinded fashion after they are evaluated using the same inclusion/exclusion criteria as well. We'll also, again, stratify across the studies to maintain balance across those key variables. A really exciting aspect of this is going back to the when we were completing enrollment with Essential 1, we had thousands of patients that were interested in Essential 1, and several thousand of them opted in to receiving future communications from us. We began reaching out to that patient population in September, and in less than a month, we had 600 patients put up their hand and say they were interested in participating in Essential 3. And not only interested in participating in Essential 3, but also were really excited about participating in a decentralized study. Just based on, again, a few thousand patients reaching out, that when we actually expand this to nationwide recruitment, we're very confident that we're going to hit our enrollment target in the H1 of 2024. So we have all of the elements in place to execute on the phase III. I've talked about the protocol, the design, patient-driven approach. Again, a lot of our success comes down to the way we work. A lot of companies talk about that, right? We actually do it. We take it to a new level. I've been at my fair share of companies, and this, and Praxis definitely is different in that regard. The one thing that I do want to emphasize is that while we are focused on the phase III design and execution right now, we are hyper-focused on NDA readiness as well. So once we have results, we will be ready to pivot and file. We're very confident in the program. As it stands, we've de-risked the endpoint. We know clinically meaningful what is clinically meaningful about mADL11. We've got an engaged and activated patient population, and we've got a motivated team. We have all the elements that we need to succeed on this program. I know there will probably be some questions, so what we'll do is I'll invite some folks up. Professor Espay from the University of Cincinnati, who's Director of the Movement Disorders Center, and Endowed Chair at the University. Rich Abel, our head of Medical Affairs for the ulixa program, and invite Marcio back up as well. Over here. Thank you. At the end. Oh, oh, sorry. Oh, yes! Good morning, good morning. Before we start, I'll just set it up. So we have a number of individuals who are also virtual, so what we'll do is ask for you to use the mic, please, when asking a question. Also, introduce yourself. We have Dr. Espay here, who can provide clinical experience also, so we'll like to ask him a few questions directly about the experience and specifically the unmet need in this space. And we have about 25 minutes to conduct this session. As Marcio asked earlier, please, please engage, and please feel free to ask questions. Wait, wait. Is the microphone on? Now it's on. Now it's on. No, it's not on. Sorry, that was me. I turned it off. Third time's a charm, yes. Sorry. Pretty not computer savvy. Yasmeen Rahimi, Piper Sandler. Thank you again for doing this great day and your perspective. Alex, I've quite a bit of questions for you. I'm really intrigued by this virtual processing. So walk me through what measurements are done through this. Is every assessment on endpoint recorded? And let's say you notice that something is not done correctly, right? So Investigator A is screwing up, it's okay. What does your team do immediately? Like, what will be in place? And then maybe reflected back, what happened in Essential 1 that obviously we didn't have that methodology, you know, in place. I guess what we're trying to figure out is, like, what will really be this impact on the efficacy. Yeah. In the variability and then the standard deviation? Yeah, so it's a great question. So I would say that this actually gives us a lot more control over that. It sounds like it might be less control because it's decentralized and virtual. But being able to access the data faster lets us query it if there is something, and we also will have a system in place that we can monitor if there's any irregularities in the endpoints. We'll be collecting everything virtually. mADL11 is just a questionnaire administered by the investigator. Same thing with PGI and CGI, and all the other endpoints as well. So, you know, I think the one of the challenges we had in Essential 1, in a brick-and-mortar type trial design, was there was a significant degree of variability between sites, even multiple reviewers at sites. So sites could have inherent variability as well. So, and investigators could have a variability. So we're really trying to control and maintain for that. Yeah. And, and maybe I'll add something there, Alex, for you, Yas, as well. So one is, it's a smaller group of investigators with larger number of patients. So they are gonna repeat a lot more, the observations, so that, that's one important point. We're not compromising whatsoever on the screening making sure those are proper patients. That's normally where the majority of the variability comes from trial. But maybe what we're not clear is, during the randomized withdrawal, we did, we actually tested that hypothesis. We wanted to make sure that virtual visits versus inside visits were no different. And so we checked the box as well. I think everything we're done for this study was deliberate. I think it would shock a lot of people to know that about 60% of all observations in any clinical trials right now are hybrid. I think people don't talk about it, but they're just happening consistently across the industry. We're taking a step forward here because we're controlling the network. We're not only controlling the actual assessment, but the network of patients being. And then the last question is, on the 600 patients that have shown interest and engagement, are you able to comment on how many of them would be eligible for the Essential3 study? Yeah. Yeah, we would. So, the way we did that was a very significant interest, as Alex mentioned before, we even started planning, because we're so close, like, to start actually dosing patients in the phase III. We went through an IRB approval process for a study. So this is actually a protocol that will go for the patients and understands where they are, are they in other medications, are common inclusion criteria. We're not pre-screening for Essential3 because we're pre-screening for any Praxis phase III study, which I think is interesting as well, because it shows the commitments to continue to work with us. All of them being every single major inclusion criteria is being tested there. What I would say is, as we continue, and by the way, today, there are more, right? There's a cut few days ago, and this keeps adding every single day. It's a very significant proportion of the patients that would be off the gate, eligible, and few of them that might, after examination by, by the experts and the RC, could as well. So gives us an incredible amount of confidence because we restricted geography for this. We're not gonna restrict the geography for the next phase. So, like, very, very encouraging. Thanks. Joon Lee from Truist Securities. Congrats on the two two two data. That looks really promising, so looking forward to the updates there. On the ulixacaltamide, how does that compare with, I think it's called, suvecaltamide? I think the structures of both are known, so have you tried any side-by-side comparison for some of their functional outcomes? And I have a follow-up. Yeah. No, we obviously did, right? You know, like, as you can imagine, I think it's proper due diligence to look across. Those drugs are all. Both of the drugs you mentioned, ourselves and the drug from Jazz, looking to all three isoforms of the channel. There are difference on the potency. There are significant difference in our favor on the metabolic profile and on the number of active metabolites, which we don't have one, and they do have multiple there. The formulation from the get-go for us is very specific to actually cover the day and the way it interacts with the channel, and I'm gonna say, if you hold for a second, and Steve's gonna talk about how drugs interact with channels and the importance. So maybe, Steve, I'll ask you to comment on T-type calcium channel inhibitors there as well. But that difference matters. We explored the dose to the maximum here, right? We dosed patients twice the actual concentration that we expected to be therapeutic right now. I know there is a hypothesis out there that those limitations will limit effect. It is not. And the only ones that actually run the experiment and have the data out is Praxis, so. Great. And then, you mentioned the study is 90% powered. So 90% powered to show what? I mean, what, what delta do you need to hit to be able to get that powering? Yeah, thank you. So it's beyond 9% power, as you can imagine. I'm sure can back calculate that from the sample size, but it's slightly larger than a 0.3 effect size. Laura? Yes, the next one is right here. Yeah. Actually, I think. He rose. Your hand was up first. Okay. All right, Doug. Doug, and then Laura. Hi, Doug Tsao, H.C. Wainwright. Just on ulixacaltamide, for the phase III program, I think, Marcio, you had initially indicated that you plan to exclude patients with intention tremor, and now it sounds like you're simply gonna stratify them, and they will be included. So I'm just curious, was that based on FDA feedback? And do you have updated thoughts on how that could potentially impact the study? Thank you. So it was mostly based on the conversation with the FDA. When you look into the study, these patients were not balanced because we didn't know their prognostic factor in Essential1. Obviously, the easiest thing when that happens is just to eliminate that and deal later in the process. But in the conversation with the agents, I think while they acknowledge that we just don't know, right, what will happen, one thing that is not clear in the field right now is the proportion of patients in the population. We strongly believe that it's very small, that proportion, but there is no definitive number there. So we put a two-tier approach, and maybe Dr. Espay can comment in terms of one being absolutely certain that is intention tremor, so even an additional check, and the second is that that wouldn't interfere with the endpoint. But the key for us here is really balance. Like, if you resimulate the Essential1 datasets, balancing the dataset, there is no issue whatsoever, right? Now, that's small in terms of what we're looking here. It's also one of our motivations to get this study larger than we originally expected. You're probably seeing that we're aiming for 400 patients on the parallel group study. So even if there is a small difference that we are not considering, that wouldn't be detrimental. I think the ultimate benefit for that is that there would be no restriction whatsoever on the population that would be treated, so expand even further the market. But maybe, Marta, could comment? Yeah. No, I would agree with what you've said. The phenotype of central tremor is diverse, so there will be differences in individuals. And that, I think, is an additional advantage of this particular design, where there is a central randomization for the two studies. So all these variables that we think may be relevant but don't know exactly how, will be equally distributed among the studies and between the placebo and the intervention. So, I'd be curious to know if there will be a biological difference according to what the clinical changes may be. We don't know the answer to that now. It'd be lovely to have some biospecimen data saved in this study that one could then get back to, because it would be lovely to find out if there might be, in fact, something relevant at a biological level from a clinical difference. At this point, we don't know what the difference is between patients who have or don't have intention tremor in terms of their ability to respond to a calcium channel blocker like this. So I think it's a great question, but it'll require more data for us to answer it definitively. Maybe just to finish on that, the power impact was the biggest issue in Essential1, not the effects. When you remove the groups with intention tremor, the drug's actually numerically better than the ones with or without slug. So we actually clinical win on that group as well. But because the effect is different on that group, it diluted the overall effects. So we'll take care of that, as we did, by just increasing the sample size. Laura? Hi, Laura Chico from Wedbush Securities. I guess, I'd like to direct this to both Praxis and Dr. Espay. For Praxis, can you just remind me, in Essential1, were assessments made at home? And then just curious what data you have, and Dr. Espay, in your experience, how does home assessment of tremor vary from in a clinical site? Thank you. Yeah, great question. It's well known that there is variability in the tremor severity and amplitude. And in fact, individuals could come to us at their best of times. It's actually fascinating when they come to us and tell us, "Well, this is not how I'm typically " So they show, and they saw a little bit and say, "Oh, I'm feeling better today." It's clear that what we capture at the clinic is never as accurate a representation of what happens at the home setting. It really is not just an artifact of just essential tremor. It appears to be very common, patients with Parkinson's disease in the same condition. Patients come to us, and they show their best selves. So the home-based assessment will likely be more accurate a reflection of what these patients' day-to-day life looks like, and particularly, what that tremor might be expressing as. It is still not quite as perfect. The perfection will be if you have some kind of a quantitative measurement across a time span. But the FDA is not yet approving that idea of measurement, so we still are at the mercy of a snapshot in time, and that snapshot in time is best illustrated by the mADL11. But if we could, in the future, I would imagine that there will be more wearable technologies that allow us to then capture that in the ecologically valid environment, which is what the home is. But having anything in the home is gonna be probably better anyhow than anything at the office. So I think that will likely increase the validity of the results at a population level. Maybe the first question are there. In Essential1, and any other time, right, that CGI was collected, the question is actually during the last seven days. And maybe there has been a little bit of a confusion there. All the physician is doing is asking, during the last seven days, how was each one of those items? So the assessment's identical. There's gonna be physician in front of the patient, and he's gonna be delivering exactly the same questions, asking exactly the same way that is in the clinic for the primary endpoints. I think the one bias you remove from that is that, as Alex mentioned, anxiety does fluctuates on those patients, and we know that it's exacerbated when they come to the clinic. So we're gonna be a lot more drug effects than confounded drug effects when you look into the house. But I wanna reinforce something I said before, we did this for the randomized withdrawal. We had a group of patients coming to the clinic and a group of patients not coming to the clinic. And there is no difference on the quality of the assessments, on the trajectory of the assessments, on how it gets reproduced. It's just far better for the patients to have a physician in front of them, but being flexible on the visits, and that's why we're going for this approach. Annette? Hi, thank you for the question. I'm Ami Fadia from Needham. Two questions from me. Firstly, just within the phase III study, what percentage of patients are going to have essential tremor? Are you limiting that percentage there? And also, was there any discussion with the FDA to have some sort of a pre-specified subset analysis where you exclude that patient population, should you see something surprising in that study? And then I have one more. Yeah. So the answer to the second part is actually very straightforward, yes. And that's gonna be very clear on the statistical analysis plan and how we're gonna be positioning. I think that is an understanding, a joint understanding between us that it's worth looking into that population. In case the hypothesis we have right now, there was imbalance tends to be a little bit more physiological than imbalance. Does not look to be a physiological problem or a pathological problem, it's more an imbalance. But if it is, would be have the ability to actually have pre-specified that population without, and we'll have enough patients because of the size of the trial to do so. In terms of the size or the proportional that population, we believe is gonna be less than 25% of the patients that have concomitant intention tremor with essential tremor, right? Not- intention tremor is more prevalent than that in other conditions, but not primarily ET that that's what we are recruiting. We're not recruiting IT patients with some ET manifestations, the other way around. They have to have three years, very clear, essential tremor, and might have certain manifestations of intention tremor. Okay, great. And then just one other question. Just wanted to understand, getting a little bit more confused about how you're gonna drive sort of consistency in evaluation in the phase III. Can you sort of talk about how, the number of investigators that you're planning in phase III, as opposed to the Essential1 study? Is it going to be fewer or, or similar? And how, how will you ensure consistency relative to Essential1? Is it training? Is it some sort of a centralized oversight? If you could explain that a little bit more, that'd be great. It's all of the above. It's about the same size of the number of investigators right now, but their general availability is much bigger. What I mean by that is, if you go to any set movement center here in the city and you ask: What is your load of patients right now? Maybe I can even ask Dr. Espay. Espay. Maybe you should ask, like, what is your relative load of essential tremor versus other patients in your practice? It's very large. This is a very large population. Now, it's interesting to note this idea of getting out. This is slightly different to your question, but it's getting out in the community is important because some patients end up not coming to us as often because they know they don't have much that we can offer them. So in some regards, there may be some nihilism on the part of patients recognizing they can come, and they get the same standard approach, but they've already often been on propranolol, they've often been on primidone, they might be on topiramate. Those are the three top-line agents, and none of them are really that effective, unfortunately. So you end up having them on cocktail therapies that we have difficulty moving up, precisely because there is toxicity that limits any potential additional benefits that they could get into. But the experience in terms of essential tremor by any movement disorders center is very high, because it's one of the most common movement disorders that we see. So we all have lots of patients. As I mentioned, I think the issue with an in-clinic recruitment might be that there aren't as many people coming regularly. They might come every two or three years to see what's new, and we have forever told them, not really much of anything. So there is zero availability of any essential tremor therapies. We don't have any. All of the essential tremor therapies we use have been designed for other disease entities, hypertension, epilepsy, and found to be serendipitously good in some level in patients with essential tremor. That's sort of how we have therapies for this condition, kind of by accident in many ways. This is exciting because it's, of course, the first ET-specific therapy designed by a mechanism that's recognized to drive the oscillatory behaviors of essential tremor. So this would be the first time that we will ever have something that actually has been designed for essential tremor value. But the point that you're trying to make, though, is whether or not there would be a number of additional- so you'll have enough. There will be a lot, a lot of the recruitment sites coming into the forefront, but the source of error that's introduced by, for instance, in my center, I have other colleagues that would rate the scales, that would be minimized, and so that source of error will be minimized. You can have the same number of investigators, but there are gonna be fewer errors that are related to the way we would be, sort of, scoring each of the elements of the mADL11. Please. Kambiz Yazdi, Jefferies. Can you remind us the nuance between diagnosing ET patients with or without the intention tremor, how you'll be doing that in the current study design? And then how will your innovative phase III study design also affect the cost of the study? Thank you. Well, so it's a good question. We are gonna have a way of cap the number of people who have intention tremor, but the point you're making is an important one in terms of the overall diagnosis of essential tremor. We do not necessarily exclude or include anyone with a postural action tremor in the hands, which is the main criteria you must have to make the diagnosis, on the basis of whether the intention tremor is present or not. So we, as far as diagnosis is concerned, are agnostic as to whether intention tremor is or isn't part of essential tremor. Essential tremor is, in many ways, a diagnosis that we make when we've ruled out other tremor disorders. We say it is not Parkinsonian tremor, it is not cerebellar tremor, it is not cerebellar outflow tremor, it is not MS tremor, it must be essential. Imperfect by all measures, so the fact that there is a mechanism that drives the excitability of neurons that are related to oscillatory activity might make that point moot. And I, I'm glad to know that there is an effect, in fact, not just on postural tremor without the intention component, but in fact, in postural tremor plus the intention tremor component. So I'm not sure that there is necessarily something we could today tell the- distinguishes these two groups. It's nice to know that there will be, just by virtue of the idea of getting a therapy out there, part of the de-risking just simply means to try to make the intention tremor patients or patients with essential tremor that have an intention tremor component, a little less, so that then we maximize the population where the effect size was the greatest. I think that's sort of the idea behind it. In some level, it's very hard. The community of neurologists still struggles a little bit as to what exactly qualifies as intention tremor, right? Because intention tremor is defined as a magnification of tremor as the finger gets to a target. So you're doing this, and if you have a little bit of a more magnification, that's intention. Well, when is that threshold where you're going from this, "I didn't see it," to this, "I think I saw it," right? That's kind of hard. It's in the eye of the beholder in many ways. We're not doing anything particularly quantitative that allows us to determine, here it is, where you have, versus here it is, where you don't have intention tremor. So it's a bit more of an art than a science in this regard. So operationally, maybe to finish the question then, and to address the cost question as well, Kevin. So we are taking a two-tier approach to minimize exactly this variability that exists in the fields. So the first assessments by the investigator, and then a confirmation by a panel, because then that is the discussion, exactly as Dr. Espay just said, would this, like, level of tremor might not clearly define, impacts the collection of the endpoints, impacts the manifestation of the disease. And that panel is completely of movement disorder, like, experts. So we did a two-tier approach exactly to minimize any bias on that regard. And on the cost question, the study, we mentioned this before, right? We were aiming for the study to cost south of $30 million. The included originally this two phase IIIs and a long-term safety study, as you might recall, still does. I think the beauty of how we redesigned the operation is a lot of the patients that would have to go straight into the LTSS, into the long-term safety study, participate on the blinded studies. So we're not adding any costs for the blinded studies. We're keeping them on drug and following and then switching to. So we're keeping the costs, increasing the size of the study. I think that is a benchmark to be followed out there. We'll take a final question here. Joon Lee from Truist Securities. I just wanna clarify, given that you will be enrolling patients with intention tremor. You will be screening out Parkinson's patients, right? And then that you won't have anyone on Parkinson's medication? Correct. Yeah. Thank you. No Parkinson patients, no clear dystonic patients, no other unknown CNS conditions that would potentially cause tremors, and we're screening all the medications as well. We've reached time. Dr. Espay, thank you. Marcio, Alex, appreciate it. We appreciate all of your questions. We'll be moving on. Yeah, we have a 15 minutes intermission. If this was a concert, it would be an intermission. I think it's just a break. It's just a break. So we'll come back in 15 minutes. Thank you so much. Thank you. All right, getting back here, so I appreciate all the conversations during the break as well. So we're gonna focus on the next part of this today's discussion on epilepsy. So to start that, I'll ask our Co-founder and Chief Scientific Officer, Steven Petrou, to come and discuss a little bit the approach. I think some of you asked, both in the Q&A and in the questions that we are having here in the break, how, right? How, how do you get to that? How do you get to, like, great results with 222, that some of the questions, and I think Steve is gonna be able to give a little glimpse of how we operate and where we are there. Steven? Thanks, Marcio. So as we saw today, an account of how we drive our phase III programs forward and the thinking that goes into that, what I wanna really talk about now is a little bit behind the scenes. Some of the thinking that happens prior to getting to this point and how. And that thinking will be sort of focused on the epilepsy programs, but it's the same concepts that we use that have driven our movement disorders program, the thinking that we do when we think about lifecycle management and everything else associated with these programs. That's me. Marcio mentioned these pillars before, and what I want to do is really talk about how they're embodied in our particular programs that I'm going to talk about today, which is going to focus on 222 and the 628 focal epilepsy program. But again, many of the things I say about that is applicable to the entire portfolio within the company. So where we started in genetics. Praxis got started following a major genetics hurdle that was passed in epilepsy, and that was the Epi4K program, and that gave us unequivocal evidence for the first time around the genetics around sporadic epilepsies. That was a key event in the company, and at that time, we understood that genetics is sure. It's gonna be, you know, if it's monogenic disorders, by definition, it's gonna be important. But for more complex disorders, we also understand that Mendelian genes are very, very relevant. The more you dig in this space, the more relevance you see and overlap between the rare and the common t ranslation, really big part about the way we think about moving programs forward at Praxis. How to—What tools do we deploy? How do we bridge from preclinical to clinical? Are there hybrids in that path going forward, whether we measure a fluid biomarker or a clinical biomarker, an electrical biomarker, a kinetic biomarker? How do we use those? How do we combine them? How do we best inform decision-making for our programs? And I'll give you an example of that. We heard beautifully from Alex this morning around efficiency and rigor. We saw innovation in the way, you know, we pivoted in a six-seven-month period to a decentralized trial system, a very interesting, you know, single recruitment, but two very different arm trials there in the phase III. You know, you may well reinforce what Alex said around the way the teams and the way of working at Praxis, with our agile framework, our drive, our relentless drive to deliver for our patients. That the patient-guided is a really important part of Praxis, but it's, of course, the genetics, understanding the clinical needs. But we also get try to understand the urgency and appreciate that and take that on board. When you talk to patients, you talk to patient groups, urgency is a big part. They want good medicines, and they want them now. We understand that, and we wanna know, how do we apply that? How do we infect the teams with that same desire to work for our patients? I'm gonna exemplify it with these two programs, both one from the Solidus platform around ASOs and the other from our Cerebrum platform for small molecules. It's relatively straightforward with a rare genetic disorder that's due to a known genetic cause, and that cause could be gain of function or loss of function. Generally speaking, antisense oligos are very well positioned to be able to either reduce or enhance expression. And I'll give you an example of that. We saw beautifully this morning from the news that Marcio shared around 222. I'll give a little bit of behind the scenes on that one, and then I'll talk about our focal epilepsy program. Not in particular the details, Karl Hansen will share that, but I'll talk a little bit about the driving behind that. How do we get to where we are today? How do the way that we work, the way that we think, the way that we use our pillars to move these programs forward? So from the ASO platform, really designed around this concept of antisense oligo intervention in the rare diseases. And first thing I want to mention is that we know, we always talk about individual gene families, and, you know, there's, you know, there's 2,000 patients here or 3,000 patients there. But when you look at the collective burden of epilepsy and developmental impairment, 1 in 340 children under the age of 16 will be impacted. And that's massive. That's massive for a devastating disorder. These aren't mild. These are kids that require constant care, they impact a huge cohort of people, of parents and other carers around them that are impacted by this. And it's a really sobering statistic to know by the end of today's session at noon, 15 kids would have been born with one of these conditions, and by the end of the day, it'll be 30 kids who have been born with a developmental and epileptic encephalopathy. Massive numbers, huge clinical need. A lot of those, of course, are driven by, you know, by de novo mutation. But we also know that there's a lot of familial epilepsy in the adult world and even sometimes in these rare cases. Collectively, there have been about 900 genes implicated now in the epilepsies. It's been a success story of neurology, I think, in really getting to the genetic underpinnings. It started with the twins, William Lennox, in the fifties. We saw the era of a lot of impact of Australian scientist Samuel Berkovic getting Ingrid Scheffer that really herald in the new era of genetics, and that mantle now has been spread across the world, and there are genetics discoveries. Now it's the time to do something about it. We've got incredible knowledge. I think the opportunity now is how do we use that knowledge and actually have impact? You know, as I said, the patient, the carer, the societal burden is immense, and I think the motivation, and the reason we do it, you know, is very, very clear. For ASOs and why the ASO program is well suited to these rare cases is because ASOs have got various modalities. You know, you can use an ASO to reduce expression, and you can also use an ASO in many different ways to try and increase the expression of the gene. Once you've got your genetic ascertainment done, once you've done whatever modeling you need to do to understand the precise mechanism of that mutation, it's a relatively straightforward fact. Okay, you know, we need to look at how we can increase the expression or how we can selectively decrease. Do we think about a broad reduction of wild type and mutant allele? Do we think about an allele-specific? You know, how do we think about this? And I'll give, I'll give a couple of examples of that, right now. So we heard about PRAX-222, and we heard about, you know, how five patients are now being dosed. And that was, of course, an idea that started in 2017 or 2016. When we first started, we still realized at that point about SCN2A mutations being causative. It was one of the, after Dravet syndrome, one of the early genes that we started to get that understanding on, and then we understood there was a way to intervene. This is a proof of concept study, essentially injecting a mouse-specific SC N2A, into a mouse model harboring a human mutation. And what you can see very clearly is that more ASO on board, you get a beautiful a dose-dependent increase in survival. These mice, untreated, die at about 25 days. And you can see on that survival curve, with a single dose or with subsequent redosing, we can extend that out, and as long as the ASO is there at a certain level, and we're getting a certain level of knockdown in the rodents, they will live for forever until the normal lifespan of this rodent. And it wasn't just in that domain that we saw improvement. If we looked at neuronal excitability by doing measurements of single neurons, if we looked at the seizure phenotype in those animals, if we looked at just their normal behavioral paradigms, you know, on, on the motor level, on the psychosocial level, and the cognitive function, indistinguishable from control. So it was a complete success story in curing these mice. We started the treatment at day 1 of birth. Even in mice where we started later, we saw some benefit. But it's this sort of proof of concept study that started some time ago, that led to where we are today with the program, of understanding how to find the patients, how to ensure it's the right patients. We developed a bunch of methods along the way that are part of the Praxis suite. Dynamic clamp for assessing unequivocally gain of function was another innovation that we did. That's all behind the scenes, and you don't hear about, but it gave us the certainty to find patients, to understand the association between the genetics, the functional readouts, and the clinical presentation. On the right panel, talking about a future program that we're, you know, we've slowly entered into this space. It's gonna be something that's ready to go when the time is right for Praxis. But what it is, it's another rare disease called PCDH19, which is a protocadherin, girls clustering epilepsy. X-linked disorder that affects females. It's a developmental epileptic encephalopathy, but it also affects mosaic males. What do I mean by mosaic? There are certain males out there that express that have some difference in the expression on their X chromosome. I mean, in this case, because of when the mutation appeared during their gestation. If it's very early, and if it comes in the sperm or the egg early, or if it happens late, you can get a different level of homogeneity within the brain. Now, what we do know, it's a disease of mosaic expression. In the females, because it's X-linked, X, you get random inactivation. Some cells express the wild type, some cells express the mutant. When that happens, you get the disorder. But we also know that there are male carriers out there that are null. So they've got a mutation that gives them no functional PCDH19. They've only got one X chromosome, so they don't express anything, and they're fine. Not having PCDH19 is a far better situation than having a co-expression of wild type and mutant. Our, our, using that genetic information, using that clinical knowledge, our program is designed to ablate PCDH19 in these females. To that end, what you can see here is, from a couple of model systems that we've run, we're screening different ASOs for human application. You can see here a very potent ASO that completely brings down expression of RNA to zero, which is the approach that we're gonna need. As I said, it's poised to move forward when the time is right for Praxis, and these are the sorts of things that will underlie the long-term strategy around our Solidus platform. Now, moving to our small molecule platform, what I wanted to share today is a little bit about how we got to where we were with 628, but also the lessons in that are relevant to everything that we do at Praxis. Now, we do this because we're very aware of where we currently are with antiepileptic drugs. This is the list of some of the more highly administered ASMs on the market. As you can see, for all the approved drugs, and cenobamate was one of the most recently approved, they were all developed, envisaged, and discovered prior to the precision genetics era in epilepsy. And that era really started around 2015 or 2016. And they didn't benefit from the knowledge that gave us about the security around genetics, around details of pathomechanisms that are critical to the evolution of the phenotype in patients. And because of that, there are limitations that many of these drugs share. One of the most telling is complex titration schemes, where you can't just take the drug at the full dose on day one. You have to start at a lower dose, where there's not gonna be efficacy, and then slowly ramp up. That's a real pain for physicians and patients alike, in complying and starting that routine and ensuring that people don't make a misstep in that. On target and off-target side effects, you know, efficacy, and there's this sort of fight between efficacy and tolerability that I'll talk about. That was really first raised by our KOL, who's with us today, Jackie French. She showed this slide or a version of this last year and asked the question: Can better side effect profile lead to better efficacy? If you dig down in that, what you can see here, if you look at the fact that almost no epilepsy medication where all patients are seizure-free. We get some benefit in some of the patients. And what happens, of course, is as you try to dose escalate, you hit a tolerability threshold. Can't give, e ven though we know, we know more so, you give enough sodium channel blockers to a person, you will stop seizures because you're not gonna fire an action potential if you block them all. But of course, that's not compatible with life. And there's this now tension between while increasing the dose to try and stop the seizures, but then starting to hit all the cognitive and all the other, you know, significant safety issues that happen. "So why can't we go here?" was the challenge. What would it take to get here, where we can fully explore the dose range and access and treat all the patients and achieve seizure freedom? What would it take for a drug to be able to do this, given that most of the effective epilepsy drugs are also acting on targets that we know you cannot fully engage? So in doing that, this is the way we thought about it in Praxis. What's the unit of function in a neuron where seizure drugs act? What's the neuron? And this is how we characterize a neuron. We stimulate it on the horizontal axis, we see the response on the vertical axis. It's called an input-output curve, and this is the input-output curve of a healthy neuron. Generally, this S shape, you stimulate it, and it gets to a maximum level. Now, if you look at a neuron from a patient with epilepsy, you see this movement of the maximum activity of that neuron into this danger zone or the epileptic range. And when individual neurons are doing this, they're firing at rates that are likely to cause impairment of the networks that they're residing in, and those networks then spread and cause the seizures that we're all too familiar about. Epilepsy is a disease of networks, driven by the aberrant firing of neurons. So of course, what do you want to do? If you want to treat this, well, you give a drug that pulls it out of that danger zone. This is what most drugs do. When they do it, in order to avoid going into those high-firing domains in that red zone, they pull the neuron's activity down across the range, and it's that effect of pulling activity, not only to avoid the epilepsy, but you're also avoiding normal function by having that gap between the blue and the brown curves. That's where your cognitive impairment, that's where your vigilance state, that's where your memory impairment, that's where all the impairments and toxicities, significant toxicities emerge. Now, what if you could make a drug that looked like the green one? That it's specifically biased towards the hyperexcitability and the disease pathology, but it spares normal activity. And the only way you can do that is by trying to exploit binding sites that emerge more frequently during pathological firing. This is the way we thought about it at Praxis. I'm showing an example here for a sodium channel, but the same type of thinking can drive the way we would think about a T-type calcium channel. That discussion came up earlier this morning with Marcio. You know, how do you engage there without having. You know, how do you dose in a way that you really impact the pathology? We know the oscillations that Dr. Espay and others are talking about are important for normal brain function, but they can be hijacked for pathology. How do you draw a line between those two things? Well, proteins, channels, they're very highly mobile. They move, and when they do move, they expose different parts of themselves. Those different parts of themselves they expose are places where drugs can interact. So when we're thinking about, for our sodium channel program here, at the top, at AB, I'm showing pathological functions or functions that are more prevalent during pathology. Persistent current is something that happens more frequently in pathology and epilepsy. Voltage-dependent current, so activity drives changes in the channels that produces new binding sites. Can you impair that function? But at the same time, can you spare the normal function, which is the red curve? And what you can see here is the profile of 628 on those key biophysical parameters. Here, we can spare the red curve because there's about two orders of magnitude over a hundred-fold difference between the potency on the things that you want to impact and on the potency on the thing you don't want to impact. We also understand that the way that the channel, the drug interacts with the channel, the speed with which it attaches, and the speed with which it detaches from the channel or the whatever protein target, is critical in meeting the demands of being able to monitor and track activity in the appropriate way. This profile is a very fast binding. You can see here, a hundredfold faster than any other sodium channel-based anti-seizure medication that's on the market, PRAX-628, and it's also unbinds slower than all of them. When you do that, you get a very potent molecule. We know potency, this type of profile is great for limiting toxicity by being potent. We also know by coming off slow, unbinding slow, that the molecule lingers enough to have the impact you want. So collectively, this type of profile, it differentiates from the other drugs, but it also lends itself to the sort of profile we were talking about. How do we meet the challenge that Jackie French put before us around getting more efficacy on the table? Well, this is gonna favor pathology. Now, what are the next steps that we take? And this is the last couple of slides. We want to translate those findings. So what models do we use to assess whether this drug is doing what we'd like it to do in the ultimate, you know, in a patient? What we do know is maximum electric shock or MES, which are really well-established model of electrically stimulating the brain and causing seizures. Drugs that work in that particular model work in focal onset seizures. And And there's been hundreds of studies that have shown a very strong correlation. But something that was less apparent, and really only emerged as the teams at Praxis dug a little deeper, that if you look at the exposure ranges that we use, that were seen in the rodents, and you can relate those to exposure ranges that are seen in people by just accounting for a bit of plasma binding, maybe accounting for some differences in the pharmacology. When you do that, what we found was that these exposure ranges overlaid precisely on the clinical use of these molecules. So, that's a really remarkable finding, 'cause we say, okay, every single time we look, whether it's a sodium channel or a potassium channel, it didn't matter, we saw this correspondence. The MES model is a great predictor of whether it's gonna work, and it's a great predictor of the dose ranges. Now, by being locked in that way, we can also compare drugs across that particular index of dosing, and Karl will show some great data on that, like, later on, following me. It all comes down to this, what's the next step? Well, we talked about how we use translation. Here, we're combining this MES model with our human safety studies to understand, well, you know, what, what are we seeing in our phase I study with the, in our SAD and MAD studies as we dose these patients? Are we seeing any AEs or SAEs that are gonna have an impact on dosing? We know on the left, these are fully from clinical studies. We know the exposure ranges, the typical anti-seizure medications, and we also know that as you dose higher, you hit a tolerability window, as I showed in the first slide. And you can see that depicted on this scale. But what we also know on the right is what a profile would be of a great drug. A drug that can span the entire efficacy range and can do that before it runs into tolerability, significant safety concerns. So we can, we can do that. That therapeutic window is a key to being able to translate. So we think this is a great tool. Of course, there is no, the ultimate is, you know, the drug in a patient. But when you look at the historical precedence of existing drugs, and you look at the profile that you could get with a drug like this, we think we're well positioned to be able to, you know, move this program forward with the highest probability of successes we can achieve. As I said, I'd love to call Karl to the stage to tell us where we are with the actual data on some of these programs. Over to you, Karl. Thank you. Everybody hear me? My name is Karl Hansen, and I'm the Chief Technical Operations Officer here at Praxis, and I'm also the program leader for the PRAX-628 program. I have the pleasure of sharing the phase I results in the context of what we believe the precision profile of 628 is gonna be able to deliver when we move the product into efficacy trials. It's been a great year. We've done a lot of exploration in the clinic in our phase I study. But before I get into that, what I wanna do is go back to what Steve mentioned at the beginning of his talk, when he was talking about our the development of 628, and the fact that even though there are a number of anti-seizure medications in use, they all have serious and significant limitations. Basically, what this boils down to is trading off tolerability for efficacy, and all anti-seizure medications can never really reach the efficacy potential that patients and physicians need. Now, impacting any one of these issues would be a huge benefit for a single medication. What we observed in the 101 study, what we were hoping to see was that the precision profile, based upon the design principles that Steve laid out and that we put to practice in the labs, was really gonna manifest itself into unveiling the ability to actually potentially impact all of these aspects. And so what I'm gonna walk you through is the phase I data in that context. And what I'm gonna talk about is. I'll show you, is that we've unveiled a very tolerable safety profile for 628. The drug reaches the brain, it rapidly achieves therapeutic concentrations, and it covers those concentrations at much higher levels for longer periods of time. And we think all this adds up for 628 to provide the potential to show maximum efficacy as we move the program forward. The way I'm gonna do this, as Steve alluded to, is go back to the MES. The MES, as Steve pointed out, predicts things that work in the MES work well in focal epilepsy. The other point he made was that the concentration of the amount of MES you can get on board with a, with a drug, also correlates to efficacy. The two examples I show you here, of a, of cenobamate, an approved drug, and 1101, a drug in development, kinda illustrate that point. These two, these two compounds have had some of the best efficacy results in phase, at phase II and phase III studies. It's also true that as you push up MES levels for them, but do titration up of the drug, you get better seizure reduction. However, both of these compounds just reach a hard cap, where they hit a threshold of tolerability and toxicity, and they can't really push the drug anymore. This has been the case from virtually every anti-seizure medication that's been brought into development. You've reached that limit, and you really can't explore more seizure reduction power. What we were really pleased to see when we ran the 101 study was that we were able to access vastly larger multiples of our MES level over 15-fold over the course of the study, with no tolerability issues and no safety concerns during the study. This is a tremendously larger amount of anti-seizure power that we have the ability to explore as we move the program forward. I want to talk a second, though, about the fact that another thing, important aspect that we confirmed in the phase I study, and that's that, 628 gets to the brain where it needs to act in order to stop seizures. And the way we did this was by examining its impact on EEG signals. So during the study, both the subjects on drug as well as on placebo had EEG collected during the time course of the study. And what we saw, using a composite analysis of that EEG data, was a clear separation between patients, subjects who were on 628 as compared to the placebo subjects. Now, not only did we see this across all the doses, but we also saw it at the lowest dose of 5 mg within 2 hours, at the first time point that we examined: 2 hours. So what this basically shows is that 628 is rapidly getting into the brain, and all that anti-seizure power that we're loading up in the blood has the ability to work where it needs to. So let's talk about rapid. And Steve pointed out this fact, that lack of tolerability for anti-seizure medications almost always leads to long and very challenging titration periods for patients. Cenobamate is the sort of poster child in this, very powerful, powerful, seizure reduction power. However, it takes about 10 weeks before you ever get to an efficacious concentration. So the first day you're gonna take, s tart a treatment of cenobamate, you're gonna have no time that you're actually protected from a seizure. 11 – XEN1101 has made a big improvement in the sense that you don't actually have to do a formal titration with that drug. However, it does have a feature where the concentration slowly goes up. They call it an auto-titration feature, so you can get more tolerated to the drug. So on your first day, you might spend 20% of that at a threshold concentration that's gonna give you seizure protection. What we saw in our 30 mg dose was that essentially, you're covered after the first hour, essentially the time it takes for you to take the pill, drink some water, and have it head into your intestine. You reach, you reach therapeutic levels based upon the MES, and they're sustained, and they're actually higher than 1-fold throughout the rest of the day. And that's, that's gonna happen throughout the regimen from there on out. But so one thing I want to leave you with, and I think we, we were talking about this yesterday with Dr. French. The limitations of anti-seizure medications in terms of their ability to provide MES power has never really been explored. Like I said, cenobamate gets to about 5-fold, no higher, in terms of safety. Same thing with 1101, with its 2.5-fold MES. What we observed in our 30 mg cohort, which was well tolerated and patients had no issues taking, was that we could actually keep patients at a level of MES at six-fold, right? So higher than what's been explored with these two medication- these two medication drug candidate, as well as any others. That's at the threshold, at the trough levels, with much more power throughout the day. So I think it bodes well for us to be able to actually really start to ask this question: How much more power can. How much, how many more, how much more seizure reduction can you get if you can just get to that point in the curve that Steve pointed out? So what I've walked you through is this, the wh at we saw in this phase I study was a very tolerable safety profile, continuous coverage at therapeutic levels, much higher therapeutic levels than has been seen before with other anti-seizure medications. 628's reaching the brain, and it's rapidly achieving therapeutic concentrations. So in the first day of dosing, you can expect to get protection from seizures. What this all sort of adds up is our ability to demonstrate maximum efficacy in the clinic as we move the program forward. And I think it's completely consistent with the precision profile that Steve outlined, that we tried to design in the molecule from the get-go. So what we're doing now in terms of 628, is we're actually running a phase IIa study, where we're exploring its effect in photosensitive patients, which have a photoparoxysmal response or PPR. Photosensitivity, photosensitive epilepsy patients basically have hyperexcitability that's stimulated by light. You can actually bring them into the clinic, and you can, in a controlled fashion, elicit that hyperexcitability, measure its range, and in a safe and controlled fashion. In this study, what we're gonna do is treat—give them a placebo, baseline the range over the course of a day, and then give them study drug another day, and then see the effect 628 has on their photosensitivity. We'll also collect PK during this study, so we can relate the blood concentration to the effect that we see. In using this, we can basically get, one, some experience dosing 628 in patients, but also we can understand better the dosing that we need to take forward as we move into the later stages of development for 628. That PPR study, we will have results by the end of the year, and we're gonna be getting the, our, efficacy study, our phase II study, going in the H1 of 2024. I wanna thank you for your time. I think with that, I'm gonna turn it back over to Steve, who's gonna lead our Q&A and our KOL discussion. Thanks. Thanks, Karl. You want to stay on the stage? Yep. Jackie French and Marcio Souza to join us on stage, and we can run a Q&A. Thanks, Jackie. So like last time, we'll do this either directly asking questions to Jackie and the team, and we can take that from the audience, and if there's any online questions as well. So let's get the mics out. I'll get that. Thank you. Doug Tsao, H.C. Wainwright. Yep. Good. So starting with 222, when we look at the data, and congratulations, I mean, obviously, very clinically meaningful responses. I'm just curious, because it did seem that the patients had a better response in that first period after the first dose, and then you saw some diminishment, over time. Which I guess is a little opposite of what you expected, 'cause we would have thought that you would have seen accumulation, which would have driven improvement in the response. So I'm just curious in terms of your thinking as to what's going on. Obviously, you have an effect that is sufficient to move into phase III, but how do you think about sort of optimizing the effect and potentially pushing the benefit further? I mean, does it require additional dosing for patients? Yeah. Thank you. So I think the first question you had to ask, when you look into this cohort, right, 5 patients now in total, is, whether or not the patients are responding consistently, and we check the box, like, big time, right? I'm actually would challenge anyone to show any other cohorts like this that show consistency, in all the patients. So let's start with that. The second is whether or not there is some variability that just accepts from dose to dose. 222 is slightly differently from other ASOs, don't have a very profound accumulation profile. So you take some of these channels from circulation, and I'm gonna let Steve talk a little bit about what happens there, and it seems to have a very, dramatic, impact on the outcome, as you've seen there, right? Well, I believe one point I didn't make on my remarks was when you look into the number of seizures at baseline, and look into the number of seizures that would happen on the three months afterwards, the total number of seizures reduction was in excess of 600 seizures, right? And just let that sink in for a minute, because there is a one last that's gonna make that patient perish, right? Unfortunately. 600's a tremendous amount of seizures. So these patients were very severe at baseline. And because of that, there is some intrinsic variability, and therefore, the second measure, the number of, like, seizure-free days, become quite important as well here. So we don't see the mean, we see a, there are gonna be a couple ups and downs. The way to fix that, Doug, to your question, is increasing the cohorts, right? We increase the cohorts, we increase the confidence, and then we get to real registration. We believe that this data set significantly accelerate our path to markets, and that at the end of the day, from a value creation perspective to patients, value creation to shareholders, that is very clear. But Steve or Dr. French. I just wanna say, number one, these seizures are extremely difficult to count because they're happening in flurries and clusters and, you know, some of them are. We even consider them uncountable seizure types. And number two, these subjects were of multiple ages, and so you're now looking at trying to reduce, you know, like, a very difficult-to-count seizure, in a child that's already had this disrupted protein for a very, very long period of time. So to me, the fact that you see a benefit is pretty incredible. One would presume that the earlier you can intervene, the better you're gonna do. So I think that, you know, rather than saying: Oh, it, you know, can't you do better? It's like: Hmm, this is pretty darn good. And probably going earlier and earlier in the course is how you do better as well. And maybe I'll just add, from the perspective of what you might expect when you're equating an ASO to a sodium channel drug. We know with sodium channel medications, you don't occupy 20, 30% of the channels when you're having efficacy. You're occupying a very small fraction of those. When you give an ASO, when these measurements were made four weeks post-dose, we would have had our steady state effect on the sodium channel expression, and if we're getting, whether it's a 5, 10, 15% reduction, that would be very equivalent, maybe even stronger than what you can do when you give a broad sodium channel inhibitor across the range that works across every single sodium channel in the body. So I think it makes sense from that perspective, the timelines do make sense for efficacy. I think just a quick follow-up. I mean, for the phase III, you plan on sort of stratifying patients by age, I think, Dr. French. Oh, hang on. Just the microphone, so the online folks. So the question is whether or not for the phase III, we intends to stratify by age, right? The vast majority of these patients, by the very nature that they don't survive way beyond, like, the teenage years or so address, like, something that is very tragic and we should be very cognizant, are gonna be skewed toward that earlier cohorts. But then we should have sufficient patients that are, like, very young, and by very young, I mean two-five, and then patients who are not, to some extent, to a balance. We don't believe as much that that would be the biggest difference here in terms of anything else, because the brain does not degenerate with this disease, and I think that's quite important. It's electric in power, like, completely dysregulated, right, in terms of the electric power. So we're not necessarily seeing. When you look into the preclinical studies that Steve showed, time of intervention did not change the outcome, so that's very encouraging. But obviously, we remain open to the, what Dr. French just said, just by logic, the earlier you interact, the more likely you're gonna have better results. I mean, I guess if I can, with a follow-up, 'cause I would think that even apart from the seizure reduction, right, the potential impact on developmental manifestations of the disease would be significant, and that you would want to dose as young as possible. Do you have an idea of, given your program, how young you could go, what your hypothetical labeling would allow you to go into? Yeah. So right now, we can go up to two, and that's how young those patients were. Now, the early access was a newborn, so that is zero. I think we're gonna have a good argument to continue to expand that, but this is up to the FDA and ourselves to discuss. So let's assume two for now. A lot of those patients, unfortunately, don't get diagnosed that early in life, either months, but not necessarily zero, as the ultimate goal here to understand. But there is enough patients in the United States and elsewhere that are on that two years or about to be two years of age, that that would be fairly easy to get a cohort filled here for a clinical study. Joon Lee from Truist Securities. I have a question for Dr. French and another one for Steve. For Dr. French, is once a month intrathecal injection commercially viable, or are you thinking of, you know, giving loading doses with maintenance, less frequent maintenance dose? Just a thought there. So I absolutely think that once a month intrathecal is viable commercially, and you know, you see now with the Stoke program, families lining up to get that. And I think, you know, there is a certain. First of all, I mean, again, you heard about this disease and how devastating it is, and the parents know that, and they will do anything in order to try and, you know, give them, their child, some hope of a better outcome. So I don't think that that's a problem. The child, you know, themselves, is not in a position to say no, unfortunately, in these cases. So really, you're talking about the parents. And, you know, it's going to get, as these ASOs get more and more onto the market, which is going to happen, there is going to be better and better capability of administering it, you know, at infusion centers, spinal, you know, infusion centers, whatever. I think that, you know, like, conscious sedation is going to, even in adults, 'cause, you know, I've heard lots of people talk about ASO programs in adults. And I think that, you know, like, I don't know how many of you in this room have had a colonoscopy, but, like, it's no big deal, right? You go in, you go to sleep for a second, you wake up, and it's all done. So, I think that mechanism is gonna improve as well. It is the future. You know, I think that it and one other thing is that in a certain way, in people with epilepsy, the idea of doing something once a month instead of having to take a pill once a day, that you have to remember once a day, has some, you know, actually, pluses to it, particularly if you don't get the same side effects that you get from your daily pill. So, yes. Great, and for Steve, you know, your functional screening platform is, it's the platform and, you know, your drugs that can selectively suppress the persistent current that predispose neurons for excitation while maintaining, undisturbing the peak, the current is interesting. How do you understand how it's doing it, your molecules are doing that? Yeah, I mean, as I alluded to, sodium channels live in membranes. Those membranes change their voltage. That voltage change causes a structural change in the protein. When that structural change occurs, it exposes different binding sites. So when you're in the persistent current mode and passing that current, you've got different binding sites available to you. When you're inactivated and you're activated, you've got different binding sites. They have different affinities. So the ability for that, that particular drug, 628, to access that site is much higher than for its ability to access the site for peak current blockade. Are you now in position of developing second- gen drugs based on the knowledge that you gained from 628? I mean, yeah, the learnings we've got for the thought that went into this can be applied to second- generation, to new drugs, life- cycle management, all of that. And we're, you know, thinking deeply about that, and then when the time is right, you know, we'll increase the level of activity in that area. Yeah. We covered this space from an IP perspective quite broadly at the points that we understood like exactly what has to be done here. So on that regards, we do have a number of programs, like we're very serious about financial discipline, as you know. So we have a number of programs that are paused at the point that we can reinitiate very quickly, that could address other areas, either for ourselves or partners, like this is a good target for pain. This is a good target for a few other things that have not been explored before, that we were not interested at this point in time, but others might be. Yes? Yes, Yasmeen Rahimi, Piper Sandler. Given that the cohort size is small, we appreciate showing the 1 patient data. Are you planning to share the individual data for that? And maybe also talk about the difference, since age had an impact, what were the age groups across the 4 additional patients? And then, have you had any chance to interact with the FDA in order to get a feel for, is this 5-patient data sufficient to move to a pivotal? Or could there be a surprise that you come back and maybe may have to treat a couple more patients to get the green light to move to pivotal. The majority of the patients in the cohort are younger than 5, as on this, so it's a little bit biased towards that, by the very nature of the disease, as we explained before. We have not yet, I think that was the second box there on my slides. That's our next step, which we interact with the agency about the results. We're just finalizing the collection for the cohort for dose 4. The collection for efficacy is a few weeks after the dosing. So dose, but then we have to get the data and make sure all the analysis are proper to go with the agency. I can tell you, we remain to be very, very confident, as I'm sitting here. One must examine precedence, right? And then when you examine precedent, normally, the way the agents look into this, and I'm by no means speaking for them, I'm just using the precedent, is whether or not the effects real? Is that unexpected for the disease? And is there other aspects that we haven't discussed everything here today that would never happen, right, on this disease? And I can tell you that, as we continue to collect data, there are aspects that never happen, right? Like, patients who never had deliberate movements, having deliberate movements, patients who never had the ability to breastfeed, they would never have because they would die before having that breastfeeding. On the benefit risk discussion, knowing a little bit about how the very dedicated servants we have at the FDA in the, in the neuro division think about this, I think they're going to be incredibly open to discussion about the benefits risk here. Can we guarantee? I think only God can do that, and we're definitely not in that position. Are we going to make sure to best- to get the best possible case there because it's real, but it's not a fluke? Absolutely. And that's coming up soon. That's why we're guiding for next year's start of the pivotal study. I might just take this chance to ask, Dr. French a question. So given your incredible experience with current medications and also your exposure to a lot of future medications, you know, what's your thoughts on the current journey of a patient first presenting in clinic? How, you know, do they currently get a treatment algorithm assigned to them? And what's the future of that, do you think? I mean, are we at the optimal place? Is there a lot of room to grow? How do we use the drugs we've got best? All right, so going back to the person with focal epilepsy, I just completed a trial, well, not just, a few years ago, called the Human Epilepsy Project, and it was an observational study where we were just looking at 500 patients, and they were recruited from around the United States, Australia, Europe. What drug were they placed on? What were their first few years of their disease like, prospectively followed? Two-thirds of them were put on the drug du jour, which is levetiracetam. Why levetiracetam? For some of the reasons that you were talking about before, because it can be started without titration, it doesn't have drug interactions, it's very easy to use, it's one dose, it starts working immediately, you can give it in the emergency room. Great. So because of that, it has been really taken up by neurologists everywhere, and two-thirds of people were started on levetiracetam. The interesting thing to us is that a year later, only one-third of the patients who had been started on it were still on it. So it was a failed approach. And the other third, approximately, were mostly put on lamotrigine. And lamotrigine is the opposite of levetiracetam, and that is it takes a really long time to get up to a therapeutic dose. There's the potential for a serious adverse event. When you get up there, for most people, it works because sodium channel blockade, I think, is the appropriate therapy for newly diagnosed patients. But most physicians were reluctant to use it from the get-go because they're worried that seizures are gonna happen during that period of titration. So if you took the best of lamotrigine and the best of levetiracetam, which potentially could be your drug, I'm saying, then I think that you would have a much more successful drug for the majority of that treatment-resistant population. And, you know, if you can imagine that person with newly diagnosed epilepsy and how long their life stays disrupted, if they get on a medication, it doesn't work for them, or they have side effects. Now, they have to stop driving again, put a new medication in place. Maybe they have breakthrough seizures, affecting their job, affecting their, you know, their sense of confidence and everything else. So to my mind, getting it right the first time and getting something on board that then will be a successful strategy is, and it's enormously beneficial for our patients. Eventually, I think it will be seen that it is enormously beneficial for cost as well. You know, one and done is gonna be so much more successful than, you know, having to have multiple doctor visits, multiple different medications, and so on. So I think that that is the way we need to go. It's a great lesson in understanding the patient journey, isn't it? And how important that is, not just for the patient, but even for the treating physician, in thinking about, well, you know, if they understand that, and they relate to that, you have a much better outcome all around. Yeah, and I mean, the doctor wants the patient to do well. You know, we feel good when the patient comes back happy and says, "You know, everything's great." And the more times that that happens, the happier we are, hopefully. So eventually, that is what needs to happen. Terrific. Along that line, Dr. French, you know, when you use drugs like Keppra and things like that, you just mentioned, what are the limiting aspects of those drugs that you want improved? I mean, I think you mentioned something like sedation before. Do you think that's an aspect of an ASM drug or ASD drug or? ASM. ASM, okay. Not AED anymore. Thank you for using that. That. New terminology. Right. So do you think sedative aspect of the standard care drugs could be improved with some of the, you know, the drugs that you're seeking to develop that limit persistent current, but do not impact on the peak current? So the problem with levetiracetam, which, of course, is not a sodium channel blocker, is, you know, why did people come off, or why did two-thirds of people. Why was it a failure in two-thirds of people? In one-third of people, it was mood, because levetiracetam is a real mood killer, and irritability and mood, and in the other half, it was failure to control seizures. And it is, when you see it, it is like remarkable, and I think this study really brought it home, is that there were people who got started on levetiracetam, and the dose was increased and increased and increased, and it was like they were taking water. There was like no impact on seizures whatsoever. They then got switched over to a sodium channel blocker, and those same people who maybe like now had an additional year of seizures that they didn't have to have, suddenly were seizure-free and remained seizure-free from that point on. So very, very sodium channel blocker sensitive. Some people absolutely respond to levetiracetam, but there is a chunk that get left behind, and you know, with newly diagnosed epilepsy, you wanna make sure that the vast majority of those treatment-sensitive patients get their seizures under control as quickly as possible. 1:40. It's time for one more question. If there's none from the room, I might just ask one final one. We made some quite bold claims around MES in our story today, and I know you've been thinking about that model quite, you know, quite a lot. So what's your experience? What's your confidence in the deployment of that in these preclinical programs? So, you know, I'm a big believer in the Maximal Electroshock test, and so was everybody else until, interestingly enough, along came levetiracetam, and levetiracetam was not effective in Maximal Electroshock, and it got everybody very anxious, right? It got everybody very anxious that we are missing drugs that could potentially be effective. And there is no doubt that that's the case. And the reason that we need better drugs that don't affect Maximal Electroshock is that, the one-third of people who don't respond to standard anti-seizure medicines, right? Now, within that one-third, you might say that there, there is, and I completely believe this story, there are probably a big chunk of those patients who, if you could just increase the dose of, you know, the drug that works on the Maximal Electroshock, you could get them controlled. But there's probably a chunk in there also that don't respond to that mechanism of which we presume is just dampening down excitation, right? And they will need something else. And we need to keep going on that search for the something else. But for the vast majority of people where just getting their excitation level down is going to solve them. What they need is a drug that's not going to give them sleepiness, difficulty concentrating, difficulty walking, you know, blurred vision, and all of the other things that go along with the, you know, the non-precision of the other sodium channel blockers. So, you know, I think you could take care of a lot of people with a sodium channel blocker that doesn't have that side effect threshold, and then the others need something else, and we need to keep working on that. I guess in that mode, MES is a good predictor in those cases. Right. It's an absolutely good predictor. 100%. Well, I think we're out of time on that note. I might just hand it over to Marcio to close the session out today. Good. Thanks. I appreciate everyone coming here and on video as well, the webcast. It was very productive. Always great to be in person. I hope you all agree with us on the tremendous growth in front of the company. I can't say how excited we all are and just heard Dr. French talk about the exceptional results we're showing today for our ASO program. Many more to come with the incredible amount of interest we have on our phase III program. I'll give you a little homework and compare with other enrollments for similar trials in the space. That's my competitive edge, like, getting in on the closing here. That is several folds. One might ask why, and our deep understanding of this community, engagement, and really focusing on the patients that get us there. It's not that we're magicians, we're just like hardworking people that try to understand the markets to a T. That's gonna get us to enroll this trial incredibly fast. And once again, no operational issues, as we never had, but very clear results by the learnings we had and what we're gonna be delivering for this community. So thanks again for being here. We have a little reception for the ones here afterwards, and, many more conversations to come. Thank you.