Thanks, Adriana. Hi everyone. Good morning. Happy post-Labor Day back to school for everyone. Welcome to our webinar with the CEO of Praxis Precision Medicines, Marcio Souza. Marcio, thanks for joining us this morning. The topic of the webinar is going to be everything that you guys presented at the IEC conference over this past Labor Day weekend in Lisbon, Portugal, including data detail from the RADIANT study, which was recently released at a top-line level. We have a lot more responder analysis and data curves to discuss today. I will be doing some screen sharing. Praxis does have these posters on their website in the public domain as we discuss them. Feel free to follow along on the screen share. We at TD Cowen can send these posters to you as well, and you can access them on the website. Sorry, I did not intro myself. I'm Ritu Borell, covering analyst at TD Cowen. Marcio, you and I have worked together for a number of years. I think it's been a while since we've had such a robust data set across such a nice portfolio of drugs to discuss post a medical meeting. Before we jump into RADIANT, which is most of my inbound client questions, of vormatrigine, what were some of the other Praxis highlights from the IEC conference? Yeah, no, I appreciate it. It's still here. It's still pretty busy, the conference in Lisbon. Oh, you're still in Portugal? Yes, yes, I am. It's fun and so on. The team is still there. I just hopped in here. I'm going to go back to continue meeting. The meeting's been really incredible. I think we shared that with all the physicians and everyone's attending. It's like a little bit over 4,000 attendees. Incredibly high engagement. I think what the feedback we hear the most, right? We heard a lot, like over 100 meetings that I participated in with physicians in the last several days, one-on-ones, is just how impressed they are with the progress and how excited. I can't tell you how many people that came in to actually ask to participate or to have access to the different drugs. It's very good to see across not only ourselves, but other companies developing drugs in the epilepsy space, how much is being done. We are, and I'm sure we're going to be talking a lot about vormatrigine. Everyone is very excited about that. Now the studies that are ongoing, the studies that are planned, as I'm sure we're going to be covering. I would say it's quite interesting, the overall interest on relutrigine and also elsunersen as well. You talked about what we presented, like there's over 15 presentations for Praxis. I don't think we're going to possibly cover all of them here. We decided, and we got a lot of questions, particularly yesterday in our receptions, like the depth of the pipeline and what we're presenting and so on. People like kind of why some of the basic research, why are you putting stuff like that? We're really committed to understand better epilepsy. Part of that is like empower, for example, and understanding where these patients, the markets, I think it's quite important for investors as well, right? It's a much bigger market than we thought. Even when we started developing these drugs, the unmet need is unfortunately pretty large, which is kind of good for us in a sense. Hopefully, we can make that smaller as we move forward. In general, having these alternatives for these patients is very needed. When you look into the conference at large, I think we collect a lot of notes and stuff like that, what I'm hearing a lot is that, yes, a lot changed over the last several years. I would say particularly if you go through the abstracts, there was a lot about cenobamate, for example, a lot about like what people, the success they had, but also a reality check in a sense and just how hard it is to achieve the best possible use with that drug and how welcoming they are for for something like vormatrigine. Even the positives, I think, come with excitement for what you're bringing next, and everyone else as well. It's not only ourselves. I think there is general excitement about drug development in this space. It was dormant for a few years, so again, incredibly exciting to be here. I couldn't have even, all the planning we did for the meeting, I couldn't imagine how much we would receive from these physicians. It's been great. That's great to hear. We're going to jump right now into the RADIANT poster. I'm actually going to share my screen as I put my reading glasses on because I'm apparently old and blind. You guys see that OK? Folks on the line, please email me any questions you guys have as we are having this discussion. I'll get them into Marcio. RADIANT, Marcio, can you review briefly the design, which we have over here, and the purpose of this study? What did you want it to show? Yeah, so if you recall where we were about one year or so ago with the program with vormatrigine, we understood what it could do pretty well. I would say in animal models that are very predictive, as we previously discussed, we knew a little bit, and then we knew a lot more on what was done in healthy volunteers and the potential to be used. We had the results from the PPR study. While those patients are patients with epilepsy, there were a couple of things that were missing for us. One is what happens instead of using, I'm going to call a biomarker, the PPR results, but we actually use the reduction in seizures that mostly affect this patient's life, trying to have an understanding of that. That was one of the objectives for RADIANT. The second was really to understand how the PK and the PK-PG relationship works in patients with epilepsy, particularly focal onset seizures. That's the cohort that is here. Of course, we have data as well, and we're going to have more data to be presented later in the year on the generalized epilepsy, and to answer that question specifically as well. I think generalized is very clear, smaller in terms of number of patients, but it's actually very large in terms of the unmet needs and the need for new drugs as well, as it relates to focal onsets, for example. We wanted to understand that. The overall dynamics of studies with epilepsy, it's always on the back of our minds as well. I think we checked most, if not all, those boxes. Of course, we haven't seen the generalized data yet, but we're going to have that soon. For all the others we mentioned, we checked all those boxes. Got it. The data from this, from RADIANT was great. We're looking here. This is the 56% sustained overall seizure reduction rate, as we can see over here. For the first time we saw this curve, it almost looks like, first of all, there seems to be this very, very rapid response. It almost looks like 50%+ seizure reductions is reached, at like one week. Is that that sort of very rapid early response? Is that a good interpretation of sort of the first few weeks of this, of this graph? Also, how rapid, because that first time point is day seven, how rapid is the seizure reduction that was seen in this trial? Yeah, no, absolutely. The process itself of seizure, right, that's how we'll always start. What we know and kind of how we use is collecting this in kind of monthly increments, right? Every four weeks, I think we round up to monthly there. Every time we collapse there. The question, and maybe I should have said that in the intro, one of the things that I heard again and again from key opinion leaders, treating physicians here is the time between seizures. Something that I actually honestly haven't heard as much before is how much emphasis is being put lately on days in between seizures, right? When you talk about the kind of, I'm going to go back to your question about what happened in the first week, in the second week, in the third week, as you are increasing this time between seizures. I think that's one of the ways to look into that. What we see right off the gate is this very rapid response, right, reduction of seizures. Because you don't need to titrate. No titration, like straight up to 30 mg in the case of RADIANT, that we really don't have that need. Again, I'm going to make a parallel with what's happening in the markets. You either have the need to titrate on very effective drugs like cenobamate, or you have to control concentrations, or that is multiple times a day. It's complex for those patients. Life is complex for them to begin with. That is a huge advantage. It is not really reliable the first week, right? We can have this reduction, but are we repeating again and again? Are you creating a pattern of response? That's why at the end of the day, the most reliable way to look at this, and one of the reasons why with the curve on the poster and on the slides, is to understand the process, right? Is the process reliable week to week? As you can see here, it is very reliable. It's getting deeper. I think what we hear as well, there are several patients in the long-term extension, and we continue to see this response. Thankfully, many of them are without any seizures right now, and that's what we want to see with this drug, right? It's not only a very rapid response that sustains, but just like we were seeing with ralutrigene before, and I'm sure we're going to go back to that, over time, you get amplification of the response and less and less seizures, and these patients are doing better and so on. Happy to see that. It's a great translation to POWER1, which is one of the posters as well, like we presented. Since, of course, POWER1 being coming up later in the year, we wanted to make sure that we had good information to use in POWER1, in POWER2, and now, once again, I think we're going to discuss in POWER3. Very happy. I would say we wouldn't rely on the first week. We had to see really this multi-week response to be comfortable. Got it. OK. That seems to be what's happening over the first three weeks. Absolutely. Yeah. Now let's talk about the second half of the graph where it does actually, I mean, it is locally weighted plot smoothing. It seems to imply a potential further decline, although there is variability around that. I guess what's happening towards the middle and end of this graph? Is that a real suggestion of deepening of seizure reduction? Are there any sort of outlier patients that are pulling the graph one way or the other with that sort of increased variability? As I was mentioning, to any given week is probably not the best way to look into this from a reliability standpoint. When you look across the curve, it is very clear, at least our interpretation, that you see a deepening of response over time. You see an increase in response. I do expect that to continue even further as we continue to develop the drug. It is a combination of multiple things, right? One, I'll say more hypothetical, is this timing between seizures. As you have less seizures, they tend to lead to less seizures as well. Kind of benefit leads to benefit. Why is that? Is it just sort of a physiological reset? Yeah, I think it is moving from the more pathological states to the more physiological states. As you have more and more efficacious drugs or treatments or interventions in general, they tend to space it out. One of the reasons why you still have such a high unmet need in epilepsy and focal onset seizures, particularly, is when they have a lot of seizures, they end up, then it leads to more seizures as well. The inverse is also true. What we are seeing here is, in a sense, expected. I think the second is, of course, why we get off the gate pretty quickly in terms of the exposure. You take a little bit of time, and it's like in the first few days, you get to a steady state and so on. Then maintaining that, and it was incredibly high compliance in this study. In general, we see these patients doing better. It's a combination of all things here that we're seeing. Again, happy because POWER1 is four more weeks. I think it gives us some extra confidence there as well. As you bring up one of the main topics of discussion around the RADIANT data is what would placebo reduction, seizure reduction, have looked like in this study. You just toggle over here to the eligibility criteria. What would you have expected that comparative placebo rate to the 56% to have been? Yeah, yeah. I think the best way to look into this, right, you've got to look into all the more modern studies in epilepsy and then ask a number of questions. The first one is like, how did they behave in similar sites with similar patients and so on? I think you have the very good example from a placebo perspective. We use very, very similar techniques like what NeuroQuant did. The drug itself did not work, but nevertheless, I think it's actually very good with their NF 1.6 isoform specific, which was basically negligible, right, around 0. All the way to, because there's always a distribution, all the way to the mid-teens, like 16, 17, 18, and so on. You've got to ask the questions, like, what makes placebo be amplified versus not? I think for the most part, what we can find and what's in the literature as well is more incomplete use of the diaries, incomplete compliance to the procedures or an ideal than a true placebo effect, right? The patients are collecting this data every single day. That's why, and I'm going to jump ahead on something you're showing there, and it's in the poster as well on the bottom of your screen, where one of the key things there, and one of the questions we have to ask is, there are different types of seizures, right? We tend to talk about focal seizures. Mm-hmm. There are more complex and more simpler seizures. I'll not try to minimize the simpler because they're very problematic to begin with. There are the generalization of the seizures or the bilateralization of the seizures versus the true focal state with them. We wanted to make sure as well that we're seeing across the board, right? Imagine if you're a patient, when you talk about placebo effect, I think sometimes we ignore the fact that the patient's just saying, I have the seizure, I have this manifestation, and I'm counting them. At the end, that is obviously, in this case, the Epilepsy Study Consortium classified the seizures for us. The patient doesn't really know how we sum these seizures up, right? This is always standards. That is a little bit of an exaggeration, I would say, that someone would be able to just even make it up in terms of placebo. What is expected, I would say, in a placebo study here, I probably would say 10%- 15%. I think that would be quite reasonable to expect in terms of median there. When you look into that, it would be an incredibly robust response to begin with. Got it. Now let's move to some of the new responder analyses that were disclosed. 22% of patients saw 100% seizure reduction in this top right in the last 28 days, with 14% being, correct me if I'm wrong, Marcio, 14% being seizure-free over the entire eight-week treatment period of this study, which means 14% of these patients had no seizures in the two months after first dose. In this study, that's correct. In this study period, OK. Did these seizure-free patients, or the 22%, were there any defining characteristics of those patients? Background meds, subtypes, duration of disease, age, anything? No, not yet. I would say not yet, not like we don't have that understanding yet. He's asking for your attention. Yeah, he's actually there meeting with physicians across the street from me. I think we debated and we discussed what can maximize the response for the drug, right? We know a couple of things. For example, we know that there were more females in this study, right? When you look, it looks like there's more females, but just proportionately, there are more females. The duration of the disease, as we call, or in the charts, did not affect. The type of medication background does not seem to affect, which is actually a good thing, right? We don't want to start reselecting patients. I think what we do have maybe more of a hint is if they are treated, like I'm going to call properly with background therapy, like it is kind of in the middle of the range from a concentration perspective. You really allow for—a physician yesterday said this to me, and I think it's a great way to think about it—it's like you've got to give space for the actual new drug, in the case of vormatrigine, to show what it's capable, right? What you're seeing is not exaggerated concentrations of all these other drugs or not toxic concentrations of these drugs, and really that space. It is associated, I'm going to say, associated with kind of the middle of the range, and the concentrations are higher. We do see somewhat of a relationship with PK-PG here for decision free. I'm going to be careful with that because those numbers are incredibly interesting and very, very exciting, right? This is 37 patients that we're talking about in total. One must be careful on extrapolating it. Given the curve described before, and then this difference between the 14 and the 22, what do you think that the ultimate seizure-free rate, real-world seizure-free rate for vormatrigine could approach? Do you think it's this around this 22, or could it climb even higher? I'm going to jump into the POWER3 of thoughts, right? I know it's a big jump to jump over POWER1 and POWER2. When you think about what the drug could do eventually, and from the very beginning, right, when you say when you dose this drug and this drug alone, and you allow for that to really have its maximum effect in this patient, we do expect like a very large number of patients to not have seizures, right? This is a fundamental mechanism. You cannot have a seizure without this mechanism. If you modulate it properly, there shouldn't be any. You might remember this. We used to have actually a very, very similar argument about relutrigine, the sister compound here in GEs. It was like, all things considered, if we start removing some of the background, and that's why I'm talking about POWER3, because you ask real-world. Yeah, like what happens a few years from now? I do think that's why there's so much excitement, because right now, patients are failing one drug after another. There is no way to actually get to seizure-free in the 25%, 30%, 40%, whatever that number is going to finally be. I know it's not going to be a single digit. I know it's not going to be on the low teens. It's going to be a very high number, because that is the progression we see as we keep. That is both a component of time. You reduce, reduce, reduce, and eventually, you don't have any seizures. That is a component of allowing the drug to work without the confusion that is in the market right now. For example, levetiracetam is a very ineffective drug, but it's used across the board. What happens when we start replacing like lev, which is like the SB2As, by a drug like vormatrigine? I think that's the question we need to ask. It's incredibly exciting to be in this position. Can you talk about how that 22% and the 14% seizure-free and eight-week seizure-free compares to other drug candidates? I know you've got a little comparative poster, or sorry, comparative panel here on safety. As we think about efficacy, you know what is this profile shaping up to be? Yeah, absolutely. It's always tricky to do cross-trial comparison, right? If anything, possibly in epilepsy, it's a little easier, right? We're always looking for the entire distribution. In a sense, the property of those distributions and how the studies are conducted, they're very similar. The patient population is incredibly similar, at least on the last few studies. Allow us to infer a little bit better. I think what we've seen in the last cenobamate, we talk about relevant drugs here. That's why we put that on the bottom, right? I think [Zinou] has a drug and should do pretty well. Cenobamate is a great drug and is doing pretty well on these patients. We're not talking about drugs that are not efficacious or should not work, right? We're really talking about a comparison with good drugs. When you look into them kind of across the board and why we said when we released the data, this is best of disease, is like if you look into those response curves, these are really the largest effects ever seen. Of course, we need to continue to see this over time in POWER1, POWER2, POWER3, and so on in the real-world evidence, as you mentioned. At this point in time, what we know is that at eight weeks, those are the best results you can see, right? We're moving from comparatively, some of those drugs, or the majority of them in the first eight weeks are single digits, low single digit zeros across the board. We're talking about here in the teens. I think that's a huge potential. We're talking about a market with about 3 million patients in the U.S. What about some of the other rates that we see, responder levels that we see here? We've got different cut points of seizure reduction, 50%, 75%, 90%. We have a proportion of patients seeing that 50% meaningful reduction by background ASM mechanism type. What does this tell you? The background meds look the same, and the response rate is, you know, time is different. If you think about the response first, right, the top charts there in the middle, like numerically, those are incredible rates. We haven't really seen anything like this. The web from the 100s to the 90. I think the 90s is quite important because it's like it kind of anticipates what's happening next, right? This time is important. That 90% essentially is the 22 from that, yeah. Yeah, you start getting a progression, right? You have whatever, 10 seizures for 28 days, and you go down to 1 while you're not free, but like you're pretty darn close to that. I think that that's the perspective. What might be the most surprising from a prescriber perspective when you talk to physicians is really the effect on top of cenobamate. I think in the last few years, people being like established this drug as a very, very difficult to use but quite efficacious drug. When we see the proportion that was in the trial, like about 30% or so, got priority, people would say, oh, that is going to be tough to show effects. Because if they are on this and they're on cenobamate, they're still having a lot of seizures. They're going to be incredibly difficult to show any response. We were the very first, we still are, the very first trial to actually have any results on cenobamate in the background. These other studies we talked about, there was no cenobamate, right? The cenobamate study was only cenobamate. The [Zinou] study, there was no cenobamate on it. The bar was incredibly high. It's a necessity, right? This is the market today that this drug is part of the armamentarium that physicians have. The fact that we are actually able to see anything there, let alone the fact that we're seeing phenomenal results, should be very, very exciting. It's like if you think about like losing weight today, it's very different than losing weight 10 years ago, right? From a GLP-1, like it's a completely, this to me is the same like way to think about it. Now paradigm here is not to do on top of carbamazepine. That is barely used in modern treatments. It's really on this more modern way to treat patients with refractory epilepsy that that's the case. Got it. We covered a bunch of stuff on efficacy. We do have a client who just has a follow-up to some of the exposure comments that you had earlier, drug exposures. At the exposure associated with the 45 mg, which you pointed out was a Cmax of 472 ng per mL, an average plasma level over the dose cycle of about 270. What's the modeled probability of seizure-free? I'm assuming, let's just go with seizure-free over the last four weeks, which is what I think of as the standard definition. If you look at that 45 mg and you are using 40, I believe, in POWER3, right? The POWER2, yeah. I'm sorry, POWER2. What's the seizure-free, the exposure data suggests at POWER2 for the 45? Yeah. Maybe to recap for the people, there was another poster that was also available, right, that talked about the exposure. That is like the box plots there for the exposure. What you see basically is linear, somewhat linear, a little bit accumulation on the accumulation effect on the Cmax, but not on AUC between 30 and 45. You can extrapolate to 40, just two level sets, everyone. We're basically talking about 50% more drug onboard. That's another way to think when you go to 40 here or 45. It is, as I mentioned before, there's an association between the higher, the top part of the distribution or concentration and seizure freedom. Now we are moving the entire distribution there, right? When you increase by 50% or so, it is not a linear relationship. It's quite much larger the probabilities of having seizure freedom there. In other words, I think when you ask me what's going to happen in the real world, like the previous question, I'm like, we're talking about a large number. It's always tricky to give you a clue. If we take that sort of background and just focus here. When you focus on seizure free, it's like the real world, in a sense, for me, is where like a large number of patients do really well with 30. They don't need anything else. They're seizure free. The ones who didn't can go to 40. Now we're talking about resolving possibly the majority of the patients, right? OK. Of course, you'll be seeing, but we're not expecting small increments. We're expecting like a very large increment if our models are correct, and we believe they are, in terms of the probabilities to become seizure free with 40 mg. That is why we're excited about POWER2 as well. Yeah. Like, we get this question from time to time from investors, like, why go to 40 in POWER2? You kind of just got the answer. Yeah, right. Right? Like we can't get a disproportional seizure free. Right now, this is the best seizure free I studied in eight weeks I've ever seen. Imagine what else is possible, right, for with 40. That's kind of the way to think about this. As we do think about the 40, let's talk about the safety and dropouts. I know when we had the top line data a few weeks ago, a lot of the discussion was around efficacy and how good efficacy was. I think a lot of investors sort of came into this study assuming vormatrigine was going to like zero out this chart, basically. It was going to be super safe. There's going to be no dizziness, no somnolence, nothing. I think people were definitely expecting a lower discontinuation rate per our discussions, although the actual TEAE, the treatment emergent rates, are much lower, even if the dropout rates aren't lower. Can you, I guess, talk to us about what drove the dropouts? Do you have specific figures right now for like AE-driven dropouts, just given that TEAE level looks lower than other drugs? Yeah. We spent a fair bit of time, as you can imagine, at the time of this preliminary readout and continuously asking the question in more detail, internally and with the sites. I probably can give you an even more confident answer right now. Number one, I love how it didn't get lost in the translation here. It is so much lower, the treatment-emerging adverse events, that we can't just brush it off. I think some people did before. You're talking about a significant proportion of patients not having a treatment-emerging AE. Which is the question, why discontinue if you don't have a treatment emergent AE? Is it efficacy? Could it be? The efficacy is good. The efficacy is quite phenomenal. I think it's a number of things. This is the preliminary conclusion I have. One of them was really the experience, I would say, of the PIs and really like getting this drug. With the drug. With the drug, right? Maybe that's a little bit of the tragedy of knowing your own drug. Know your own drug, I think here, like it's a very potent drug. There's an expectation, even when you consent to the patients, they are a little bit more fearful, right? It's like anything that happens in my life is because I'm participating in this clinical study versus it's ironic, right? Because when you have placebo, they're like, I'm not sure I want to be on placebo. When you don't have placebo, they get a little bit more on their heads. We got a little bit of this feedback. It was somewhat concentrated in a few sites. One hypothesis we have, and I think we tested now this hypothesis thoughtfully. It seems to be that really the counseling of the patient makes a huge difference here. The counseling of the patients around side effects and like what. Around the trial procedures and side effects, really, in a sense, being available for the patients as well. To the point that, and I mentioned this. The patient support, essentially. The patient support from the site personnel, if this was widespread in all the sites, I would say this is probably more related to drug. I'm not trying to make up an excuse because it's really not, right? I think a lot of the focus is like figuring out what happened here and making sure it doesn't happen in the POWER1 or POWER2 studies. Exactly. So yeah. That is where I was going to go. That is where we're going to go. I know this is not a regular call, but it was another regular call that I mentioned. It's like on POWER1, it's much, much lower. Of course, it's ongoing and so on. We are not done on those number of patients. Are the sites that you mentioned that didn't have maybe the best patient support, are they in the POWER1 or POWER2 studies? I would say that's what makes a difference as well, right? I think that that's not a complete overlap. It's that it's some overlap, but it's not a complete overlap. People learn as well. OK. Yeah, they learn by, like, willingly or not, to improve the overall support. We're glad to see it reflected on POWER1, because we really, I agree with what you just said, that it should be much lower in general. I think that's what you're going to see in the future. Got it. OK. When we think about dizziness and somnolence here, can you talk about the grade? Can you talk about the transients? Yeah, yeah, absolutely. Absolutely. Yeah. The vast majority of those patients, and we talked about this, right, they are moderate and all transients, right? That's why I'm saying. Transient, like how transient? A day or two oftentimes, yeah. Sometimes as well, it's just like the time of the day, right? As we know, that is potentially like the Cmax effects with these drugs. Like you said about being clean and it's like zero off the chart. I would be very worried if there was no side effects. Very, very worried, right? It's a potent neuroactive drug you expect to see in combination with several other drugs, like two, three other anti-seizure medications, all of them with profiles of side effects. When you look across the board, it is like, remember, 30% or so of the patients were on cenobamate. You look into the rates in cenobamate, the fact that they're actually lower, it's kind of a little bit of a miracle, right? Because those patients would have something, a big proportion of them. Again, not unhappy with the side effect profile in general, actually. I think the only part we could do better, and we were doing better, was really on the discontinuation part. Got it. OK. Holistically, Marcio, as we look at this poster, as a commercial guy or former commercial guy, now CEO, obviously. Once upon a time, once upon a time. Once upon a time, when I first met you, as you look at the commercial, as you look at the commercial profile, what profile do you see that's emerging that is compellingly differentiated from other options that are in the same sort of treatment line for these patients? Yeah. It's funny, right? If you try to break down and ask what would the, what is the minimum profile this drug does, and what is the maximum or the ideal target profile this drug does, and you're looking to the minimum profile, let's assume that this is the minimum, for example. It is already probably dominating the refractory markets. When you look into that, we're talking about $1.5 billion peak sale, and like massive, in a sense, so amazing, right? What can be done? What is really exciting, and we're a little anxious, actually, when we start hearing this, that we would present this to physicians, particularly like someone has to prescribe this drug. They have to be really convinced and excited about it. People really are. I think what we heard the most was, wow, I'm finally going to have a way to really replace levetiracetam. There has not been a drug in the market or developed that you would move, right? You would start, and that's how it started here. It's incredibly competitive for the refractory markets. Because it's just like levetiracetam is such an intolerable drug. It is very easy to give. In a sense, for tolerabilities, as we know, talk about a real profile of the drug, right, from a side effects profile on the psychiatric side, is very problematic for these patients. It's not a very effective drug to begin with. You use as first line because that is kind of, it's relatively easy. That's what we hear from physicians. Here you have a drug that is easy and is highly effective. Yeah. That combination of being convenient, I'm going to call, but highly effective has not existed in epilepsy treatment. When you think about, again, real world, down the roads, the potential to combine the use across the spectrum of epilepsy, it's even hard to quantify. There has not been a drug that's been there with $3 billion+. I think that that's the number we come up with when we model. Got it. POWER1. POWER1. Let's review quickly. How's enrollment going? Are we still on track for year-end? You know, again, based on this data, right, and what you said about the 10%- 15% potential placebo reduction rate, what should investor expectations for seizure reduction be out of POWER1? Maybe first on the enrollments, right? We haven't made any announcements yet. We will soon. I think we should expect that things are going really, really well. What we mentioned before, I'm going to say it again, is I think this sets up the stage for what to expect. At or better, I think we can confidently say that's kind of what we're expecting. At or better. At or better At or better than the 56, the 22, both? Than the 56 or so. That's the easiest, in a sense, to benchmark and might be the most important at this stage of development. I say that for a combination of things, right? One is the time, like we talked about the shape of this curve, like over time, and the fact that when you look into the concentrations that are achieved from a drug concentration in circulation, we're right at the exposures that give a high effect on our PK-PG modeling. High level of confidence is always a study, blinded, and so on. I think we should expect very clear effects on a placebo-adjusted basis. Got it. POWER2, what about since you're going up in dose on POWER2, how should people be thinking about that data relative to POWER1 and RADIANT and the timing of that data? Yeah. POWER2, we mentioned we're starting right now in the last month of Q3, right? POWER2 We're talking about starting right about now. the incredible excitement about participating, I think a lot of the sites are coming to us and saying they're going to participate in as well, right? I think we're obviously selecting the sites. This is going to be a larger study. We want to make sure people stay hungry there as well in terms of participation. What we figured out is that there is really a very systematic way to review this patient's profile, to work with the sites to recruit this consistently, patients with epilepsy. We're fairly comfortable. It's a lot of work. I'm not going to say it's not work. We're not afraid of recruiting another study or two studies or whatever it is. In about 10- 12 months, recruitment here is probably what is going to be needed for As you start right now, we could expect to be finalizing late next year. Second half of the year. Yeah. On the efficacy, we mentioned this before. Of course, if you're going to have higher response, you should expect an even better response on the 40 mg. It should be pretty similar on the middle dose and that should represent the package, right, between and that would allow for a regulatory submission. It comes with that impact as well, potentially getting this drug submitted, like let's say in the next 18 months or so to an NDA, which is really exciting. How is the enrollment profile looking, patient profile looking versus RADIANT? Yeah, from an enrollment perspective, from a recruitment perspective, a lot of the sites actually had both, as we mentioned before. It was actually patients coming to RADIANT, and then RADIANT done, and then they go into The huge advantage of having multiple studies in some of those sites. I would argue very, very, very similar. OK. The profile. That is based on what you're seeing, like the patient. Yeah. Based on what you're seeing, like in terms of the, because they're the same patients at the end of the day, right, that are coming here. One of the things we learned, and you might have seen this to take a little detour into the EMPOWER poster, is patients come into the site and they're like, you know I had three seizures the last month. For most studies, you would be like, let's see how you do and so on, and if you would qualify. Actually, when you start counting, it's significantly more. I think because no one systematically counts every single day. What we're trying to do more and more is just say, put them in a diary right away. These are electronic diaries now, not paper diaries. Electronic diaries. A lot of the patients historically being on paper diaries. Paper is a little trickier, as you know, in terms of making sure they're being compliant. We have an electronic system. You can see the compliance, which we require to be over 80%, right? 80% of the days with entries, which is basically gold standard for efficacy here. We see way beyond 80%. That's the good news as well. As they start counting, you see they're having far more seizures at baseline, which might be the simplest thing we've done to ask everyone to bring a diary, and maybe the most effective to actually get recruitment. The sites, they're all the same size for all these studies. They're all the same people, right, doing these studies. They're just getting the patients through. Understood. All right. I think we've covered vormatrigine. We had. I think so too. Yeah. We have one last client question about an IV formulation. Yeah. What are you thinking there? We are asked all the time about this, literally all the time by actually the regulators in Europe and as part of the PEP and in the U.S. by physicians all the time. It's quite insoluble, the molecule. There are ways. We're working on it. We believe we can solve this problem. We're actively working on an IV formulation. It's not there yet, but we believe we have what it takes to get it through. Got it. All right. Let's move to relutrigine now. How is the EMBOLD study going? What should we expect to see from that second cohort? Let me switch over to that poster. Here we go. Yep. We talked a little bit about EMBOLD before, right? Reflecting on our guidance, I think what we've been saying is a little unusual. We said no later than the first half of next year for the readout, and it's basically on the pace of enrollment. That's what it has to do. You can imagine when we guided for seizure reduction here, we're talking about 25% as being the actual goal. We are about double of that. When you look into about one year after, like 11 months from here, that is 90%. It was completely like complete disease modifying, right? You should see the communications we get from sites about these families. It's just incredible what this drug is doing and how it's changing. Not surprising there was a lot of interest on enrolling or on participating on this study on the second cohort. I will say stay tuned. I couldn't be happier about the pace of that study. You might have seen we were granted breakthrough designation. I think there are opportunities here with the FDA as well to potentially bring this drug faster to the markets too. We're exploring all of that. I'm going to be talking more about all of that soon. It allows us to open the EMERALD study. I know we're talking about EMBOLD. Since we don't have unlimited time, I'm going to try to pack EMERALD here as well. EMERALD is like we are not adding, for example, new sites or anything like that for EMBOLD. We just can't, right, based on where we are. EMERALD is open in the U.S. It's imminently going to be open in Europe. It is very, very interesting because I think the message we've been getting to the sites and the message from the sites, number one is just how excited they are about this study. The second is almost like it is very, very fast what's happening in the U.S. right now with EMERALD. The enrollment. Very fast. OK. It might be the fastest interest on my study we ever had or the largest interest on my study we ever had. We're trying to pace a little bit all the regions, right, to get all these patients in. You feel confident in the quality control of the screening and stuff like that, despite the fact that. It's even more interesting here too because we're talking about like centers that have these patients since they were born, basically, right? We're like seeing like this, not naming the centers, but it's all places we know. Like you would bring your kids, and I would bring my kids to when they were kids to like if we need this like excellent care, like level four care in epilepsy. These patients, I think, differently from the full-concept seizures we're talking about, they're all in diaries. They're all like looking to this. There's just nothing that controls their seizures. It's incredibly exciting. The process itself is very similar in terms of the medical review education. We do that independently, as you probably know. You are correct to say we got to ask the question all the time, are those patients appropriate? It's incredibly stringent, the inclusion and exclusion on all these studies, right? I think these families and the physicians know. That's why they're excited about something that can really change. When you talk about seizure reduction, a lot of people are like, well, it's only seizure reduction. I think it's a little bit idiotic to think that way, right? The key thing here is the seizure. When you reduce that by 50%, 60%, 90% or seizure-free, it's completely life-changing for those patients. Got it. We only have about five minutes left. I do want to touch on elsunersen, which we have not discussed as much recently compared to vormatrigine and certainly relutrigine. In the posters, you shared a couple of emergency access examples that were quite compelling. What are you seeing in these children? You just started the pivotal study. Can you talk about the data flow out of that program? Yeah, absolutely. There are two cohorts on the current study. I'm going to go back or share a little bit an experience with one of the emergency access, which warms my heart. The study is open right now, the phase three. We have the second cohort of the previous study that is basically closed. We're going to release that as soon. We haven't seen the data. I haven't either because that is randomized one, two, three. I think in overall, the experience is really fantastic. I met with one of the investigators actually right before this meeting in the Congress who has a fair bit of these patients on the second cohort. It was very, very nice to hear how the experience. Most of these patients transitioned to the open label, so we can talk more about benefit and so on. The pace of enrollment is only 40 patients, as you know, on the first cohort. There's a one to two-year-old and then a zero to one cohort as well. I would say right now, there's probably like actually a queue on the sites in Europe and the U.S. and Latin America to enroll in that study. Could you over-enroll this study? Would there be a benefit to it? Could you just put people in an expanded access? I think we're probably going to put people on an early access type of mechanism. I think there's a very high interest from the agency as well that we bring this data back. If you put more patients, it would probably take longer, and one wouldn't be able to unblind. We're probably not going to do that. We're happy with the interest there, with the overall view. You mentioned some of the emergency access, right? It's always tricky to approve. I think our clinical development folks and safety review this case before they bring it up to [Siv] and myself and others in terms of the final approval. It is always tricky. These are very fragile kids and a drug that is in the clinic. They can't be eligible to the trial to participate. When you see things, for example, the latest emergency in the U.S., which is not completely reflected in the updates, I'm going to just throw it out there, kids in status, like two weeks old, and really being able to, the FDA, phenomenal response, allowing that to happen and so on. A few months later, that we are now, and the kids not only have no seizures, but developmental milestones are being gained. It really shows what this drug can do. You might have seen, I'll leave it like that, as our last minutes, that there was one of the experiences on the combination of relutrigine and elsunersen as well. What's the potential there? There is only so much on any disease state that one drug can do, right? For some patients, for those incredibly severe, this patient was having significant seizure activity intrauterus, right? This one patient in Germany. When you hear about not only the seizure improvement, which seems to still be incredibly severe, but now the ability for the family to interact with the child, it is incredible, right? We could do a lot of the seizure reduction, not being in status, not being readmitted to the hospital with We really didn't have a lot of the other manifestations that are probably secondary until you added on that case. We never intended to start thinking about combination this early in development. It certainly does show what is possible on these drugs in the future. Got it. I know we're at time, but I just have a last question about what to expect at the end of the year, in December, probably at epilepsy. Do you guys know what's been accepted at AES yet? No, they have not. We have several presentations accepted, but not the RADIANTs yet, right? Let's assume it will. I think we can assume it will as late-breaking presentation. What we would be seeing there is like the full cohorts or like over 60 patients with focal and the cohort of. And generalized. Generalized, and I think everyone's going to be quite excited about seeing that. A year from now, it's going to be? A year from now, we would have long-term data and on the European Congress, right? There is an alternating International Epilepsy Congress. We will have POWER1 and the long-term for that. For AES as well, you saw based on the client's questions, you got a lot of questions about the modeling as well, right, for POWER2. I think people are going to be starting asking questions about POWER2 this time next year. We intend to put a lot more of the modeling data out as well, like around AES and AEN and so on. Understood. Great. With that, we are over time. Marcio, this has been very helpful. Thank you for all your patience. Likewise. Dealing with me on the RADIANT poster and all the questions coming in. Sounds good. If anybody has any other outstanding questions that you guys didn't email me, please feel free. I will follow up with Marcio and Tim, Athena and I, and we will get you those answers. Thank you, everyone, for joining us this morning. Thank you so much, Ritu. Thank you, everyone.