All right, I think we can get started now. Good afternoon, everyone, and thanks for joining us for our virtual fireside chat with Marcio Silva, CEO of Praxis Precision Medicines. Before we begin, I need to read our safe harbor statement. This call has been arranged by Truist Securities Research for use by institutional investors, as defined under FINRA rules. If you're not an institutional investor, please disconnect at this time, and please see our website for our equity research library and the required disclosures. Also, if you have any questions, can you hear me, Marcio? I can't hear you. Also, if you have any questions you'd like me to ask management, just email me at joon.lee@triust.com, and I'd be more than happy to ask them for you. All right, I hope you can hear me now, Joon. I can hear you. Let me just ask because one of my associates said that they can't hear me. Okay, I think they can hear me now. Awesome. All right, thank you. Thank you, everyone, for telling me that you can hear me. We had some audio. Let me just quickly read the disclaimer. This call has been arranged by Trust Securities Research for institutional investors, and if you're not, as defined under FINRA rules, if you're not an institutional investor, please disconnect at this time and see our website for the required disclosures at the Truist Research Library. If you have any questions, email me at joon.lee@truist.com, and I'll be more than happy to ask them for you. Marcio, thanks for making the time. You had a busy day. Of course. And today. Just a bit. Yeah, just a little bit. You top-lined data from the open-label trial of Radiens evaluating for myasthenia focal epilepsy. I want to dig into the patient disposition, the efficacy that you top-lined, the tolerability, background therapy, and the upcoming data at the IEC as well as Power 1, 2, and 3. I want you to start off with maybe a five-minute recap of what you shared yesterday. Yeah, absolutely. I appreciate being here today after great data that we presented on Radiens yesterday. Maybe I'll start talking a little bit about the market itself, right, Joon, because maybe that's where this all started and then how Radiens and Power 1, 2, and 3 would play a role here. We know, I think we all know how large the epilepsy market is, like about 3, 3.5 million, depending on how you look into the number in the U.S. Of course, proportionately more outside of the U.S. Many drugs have been attempted, many drugs are approved to treat epilepsy patients. Unfortunately, I would say on one side, that is really not a solution right now. Not a drug or a set of drugs that address the majority of these patients or even the minority of these patients. On that side, fairly unfortunate, there's a lot of opportunities there. On the other side, fairly fortunate, right? What we know is you can come into this market and, as we're looking for, for relutrigine, make a real impact with a drug, and it's, by no stretch of imagination, the only drug or the only set of drugs. Like if you had three other epilepsy drugs for focal epilepsy, it would be interesting to develop all of them in a sense because the market really can accommodate a number of drugs. I think that is a very interesting motivation because what I see a lot going on in conversations when we have way less with the neurologists treating these patients, but a lot more with people like us in conversations like this, is this impression that there's a race for the last few patients, right? Maybe one day that's going to be the case and you're going to be like one way to cure epilepsy. I think right now we're really trying to get better and better as these drugs are treating more and more of those patients. In that regard, incredibly happy on making a step forward. I think the second incredibly positive thing about yesterday is it's a little bit of a wider water-like divider for us, right? Moments or shared moments where we were very bullish about everything that happened before yesterday with relutrigine in terms of the PPR results, all the preclinical data, all the phase one studies. We always said, and until yesterday, I would still have said that we need that data in focal patients to really be able to like say this is a drug that is highly effective in focal onset seizures. I think we are now at that moment that we can turn that page towards really saying that quite confidently. Now, from this point on, it's how to bring this drug to patients in the broader markets. Looking to the profile of this drug, it is one that really sets itself to keep moving lower and lower on the adoption. I think everyone starts. One could argue rightly so. I'm not sure if I agree with that on these hyper-refractory patients. They are important, but they are a fraction of the markets. They are a small fraction of the market. They're incredibly valuable from a revenue perspective, but they're still a small part of the markets. Moving lower and lower would be ideal. If you go from an external reference, and then I'm going to bring an internal reference, right? Looking to the Human Epilepsy Project One that focused on focal onset seizures, that was the two that focused on generalized. There are two major conclusions there that I think are super interesting. There are many, many conclusions, but I'm going to focus on two of them. One is there is no doubt that modulating sodium channels is the most effective way of treating focal onset seizures. That's from that set of publications for that large study that was done. It's still ongoing. The second is the cycle of ASMs is not the best thing for these patients. When you put those things together, it's quite nice to have relutrigine to be able to add to that, to replace many of those drugs right now and to move towards really eventually, as our vision, and we're going to talk about that on Power 3, to really be the drug of choice there at the end. Do we need to get there to be a multi-billion dollar drug? No. We don't need to show many things that people oftentimes ask us to. That is the vision, and that's the path towards that position. The second piece, and I'm going to get out of the soapbox here, is the fact that we completely replicated that with our own data, right? We run a fairly large claims analysis, about 0.5 million or so patients in the U.S., and it matches almost one to one in terms of the use of drugs. What they stay the longest are on sodium channel blockers. What we see, patients cycling through, about 60% or so of the patients add a second drug and then a third drug and a fourth drug. We see them cycling a lot. It creates that nice market dynamic from a revenue perspective that you can always add another drug. It It doesn't really matter in a sense, but a huge opportunity for a drug like relutrigine. We're going to talk about the results, but I wanted to set up a little bit of that market opportunity that is in front of us. Thank you, Marcio, for that. We will use some slides that you shared yesterday to go through some of the details of the results. To your point, the centrality of sodium channel modulation as the cornerstone of epilepsy management was, you know, I mean, 81% of the patients in Europe had background therapy at a sodium channel blocker and actually managed to show pretty remarkable seizure reduction even on top of that. I don't know how your relutrigine, which modulates sodium channel, could even work on top of an existing sodium channel blocker because the receptor must be already occupied. That's for another conversation, right? That was important. I mean, you know, I think, I don't want to like run this too much, but are you going to need Power 3 to register? Or is that something that you might, you know, after submission? Yeah, no, not at all. I do want to take a little bit of a segue from what you just said, right? A priori, if you think about like quote unquote rationally, we're going to pretend we're rational animals as humans, like adding the same mechanism, right? People talk about orthogonal versus non-orthogonal mechanisms and stuff like that. It wouldn't make sense, right, that you actually have so much more efficacy out of that. Take a step back and ask the questions like if this thing, I'm going to call relutrigine a thing for a second, that we are putting on top of other things that are similar, are not really dissimilar, it's not really different, why would you show? Let's take it from a more basic level. We see that as yet another proof point on how different this drug is, and therefore its ability to continue to grow the market and to replace certain drugs and to add to other drugs. At the end of the day, it's not going to be a magic or silver bullet. This thing, there is space for a lot of people and there's a space for relutrigine for certain. Got it. All right, I'm going to share a screen so we can actually. Please do. Let me see. This is a slide from yesterday's data presentation that describes the patient disposition in the Radiens trial. 99 patients were screened, of which 61 were dosed to date, and you presented data from 37 patients yesterday. Now, how many of the 61 patients that were dosed and the remaining 24, how many of those are still focal epilepsy and how many are generalized epilepsy? Yeah, I'll be the first one to say it probably could have been a little bit more clear here. Yeah. So the. Here's a chance. Here's a chance. Here's the chance. Thank you for that. The slide is entirely about focal onset seizures, focal epilepsy, right? The way I'm going to walk from left to right is because I think it's going to be a little bit simpler. When we set up to do this, we're like, we're going to give about 35 or so patients, right? 50.7x. We start counting, right? One, two, three, 37. That's how that 37 was defined, was the 37 completers at the time that we did the data cutoff on the 25th of July. That is the first 37. Now, between the time that we actually said to the sites, you know, we're pretty close, like we're getting there to the 35, and when we actually stopped completely recruiting for focal, and I'm going to go back to generalized, there were significantly more patients on that process. The process takes anywhere between 28 days and 56 days to screen these patients. You see that you can just not sometimes you stop a running train. That's on that period that were these other patients that have been started dosed. It's anywhere between a little bit over a week to like about four or five weeks that these patients would be dosed. It was a mix of exposures, but pretty significant exposures for the other patients here in the difference between 61 and 37. That's why we included that on the safety because we thought it was very important. Of those, at that point in time, 99 had completed the screening. What we expect is like within those and a few more that are not included here for generalized, we would have like a general update at AES later in the year. That is the box on the leftmost side of this slide where we expect with the focal, like 61, 62, 63, whatever the final number is there. The difference between that and 75, that's where would be the overall. The difference is the generalized patients, right? The primary generalized patients. I think the bottom line here is we're not only delivering what we said we would for focal, but really show the incredible interest for this drug and for this study. Just the ability to recruit, I think that is one of the many urban legends out there. It's just how hard those patients are and how difficult it is to recruit patients. Of course, it's not easy and requires a lot of attention, requires attention to quality. It is completely doable, right? Like as we're showing here. No, I mean, just to nail down on the details here, by in fourth quarter, you'll have data maybe at AES on about 75 patients. That will include the 37 patients top-line yesterday with longer follow-up beyond eight weeks. There may be more focal epilepsy patients included in the AES presentation maybe. Then. There will be, yeah. There will be, yeah. What's the breakdown of generalized versus focal when it's all said and done? The intent here is to present all, let's call 75 patients at AES. Of those, a little bit over 60 are going to be focal onset seizures. The difference there, let's call 15 for the sake of the arguments right now, should be generalized. Is it fair to assume that the 61 patients that were dosed to date, that's all FOS? There are generalized patients. They are not included in the 61. All those 61 that are here are focal, sorry. 61 patients dosed to date are focal, but they were not included because they haven't crossed the eight-week follow-up? Correct. That is the only reason. Oh, I see. There were 37 that had eight weeks' worth of dosing data, and then 24-ish that did not, that had less than eight weeks. Yeah, anywhere between one week and about five weeks. Gotcha, gotcha. Subsequent to that, you started adding generalized epilepsy patients. Mm-hmm. Up to 75%. We're well on the way there. That's very clear. Thank you for that. All right, and then, you know, let's get into the back, the sort of the demographics. 81%, as we discussed, were on sodium channel blocker. 65 were on, is it synaptic vesicles or Keppra? Yeah, yeah, that's right. Keppra or Briviact then. Keppra modulators. Is this typical of, does this represent like typical patients in the epilepsy, focal epilepsy, what the kinds of drugs they're on? Yeah, absolutely. We showed one slide on our claims work here, but it's actually a very extensive analysis, not only of the type of drugs they're in, the duration they're in, how they cycle, what's the decision triggers, and stuff like that. I can comment a little bit about the U.S. market in details there. This is fairly typical of the market. Normally, the vast majority of patients in the U.S. start with Keppra or with levetiracetam. The vast majority of them fail, right? That drug has the lowest response rates of any drug that is widely used here. It's not unexpected in a sense. It's a very easy drug to be given to patients, and that's why it starts there, one of the reasons why it starts there. They move normally to a sodium channel blocker in that case, and they go back to other things, they come back, they add sodium channel blockers. The steady state, if I may call it that way, ends up being something like this, a makeup that is similar to this. I'm not an expert on epilepsy, but just being a biotech analyst, looking at other trials, if I were designing a trial, I would have avoided patients who were on sodium channel blocker because it seems redundant. You're not a blocker, you're a modulator, okay? That's a nuance there. You work at the sodium channel, and you have patients already on sodium channel. I would have avoided them and actually tried to not enroll these as an exclusion criteria, but you haven't done that, and this is actually a demographic. Yeah, I think once upon a time, maybe some people still believe that there was this idea that people were responsive to a mechanism, right? I think for some patients, it might be true for certain mechanisms, but generally, you're trying to stop the seizure. I think that is one thing that we can say pretty confidently. You cannot have one if you properly modulate sodium channels, right? They're fundamental for initiation and propagation of seizures in general. What we know as well, right? They are on all those things, but it's not working, not completely at least, right? You look into the median seizure there at the bottom, like this is very high. This is fairly refractory in terms of refractory seizures, right? It's not only to a given treatment. Most of the time, and we made this in another slide at this point, but maybe just to make it a little bit more nuanced way, there is a lot of stacking here. The stacking of different drugs is not necessarily what one would call rational, right? They're very much empirically driven at that point in time with the patient in front of them. Oftentimes, it is driven by whatever they can do at the moment. When you look into a drug that actually you're very confident can stop seizures, as you've seen on the results, I'm sure you're going to go there next. You kind of have to ignore this noise about what is in the background and ask, can we do that? Can we actually, and of course, 10 steps ahead, that is the easiest one to replace, right? If you're thinking about Power 3, for example, this is a very obvious replacement. There is not a lot of other markets or a lot of drugs in development that I know of that the easy replacement is 80% of the markets and the drug is going to be better. I think everyone here in this call knows how to do math. You can just imagine what kind of markets that can be. All right, I'm getting email questions, but I'll save all that for the very end because, you know, we need to move fast. Just one quick point I want to ask here. You know, were patients on, you know, in this slide, were there patients who were on more than one sodium channel blocker? Absolutely, yes. There were patients on two sodium channel blockers, a fair bit, actually about half of all the patients on sodium channel blockers were on two. There are even situations patients were on three sodium channel blockers. Obviously, adding relutrigine on top of that. Okay. I mean, if something works, I mean, if you have one sodium channel blocker that works, is there a point to having other sodium channel blockers or sodium targeting drugs on board? Yeah, I would say absolutely. I think when you talk to the physicians who are prescribing these drugs, those are real patients. They are real physicians behind it. They are not dumb, right? They are actually trying to help these patients. They're very smart, actually. There are limitations on all these other drugs, right? Like we look into lamotrigine, there are certain limitations from an immunological or immune response perspective. There's so much you can do with that. Or lacosamide, there are other limitations. Even older generation drugs like carbamazepine or zecarb, all of them, I think they're trying to do the best with the tools they have at hand. Those tools are suboptimal, but they are really well intended. They are really trying to help these patients. For the most part, they are helping these patients. That is, it's not to say that there's not a better way to do it, but definitely, they're all trying to do the best here. One more point, you know, we will get to this towards the end, but you talk about trying to take off drugs, like, you know, to avoid AEs. How do you go about picking, like, let's say the patient is on three drugs, like one, you know, Keppra, sodium channel blocker, GABA, which one do you take off? How do they, you know, it seems like a very imprecise. Yeah, we can get there. Maybe we move a little bit, talk about the review. That's okay, Joon, since you said you want to manage the time, I'm going to help you manage the time. All right. I mean, look, this is, there's no controversy here. I mean, you saw this 50% reduction in 60% of the patients, and you see a median of 56.3%. Again, you have week one, week eight response, improving over time, and, you know, 22% seizure freedom. That's really, you know, the impressive aspect about the drug, which is that in the last month, you had like seizure freedom, even on top of cenobamate, 30% of patients. Anyway, before you move on, like, have you, are there any like particular response based, have you stratified response based on background therapy? Does this work better in patients not on sodium channel blocker or with sodium channel blocker, with or without cenobamate? How does that efficacy look? Yeah, so we'll go there in a minute. I'm just going to make two points about the previous slides, right? One, when you look into this, these are all patients. All 37 patients are included here on both panels, right? When you look into the overall median, like 56.3, this is like considering every single patient in the study. It does not remove any of the discontinuations that I'm sure are going to look into that. I think we got questions before. It's like when you look into the overall median, this number looks bigger, right? Because the points for all of that and what's happening, obviously, we always get a little bit impacted by discontinuations and things like that. The same thing with the more than 50% response on the right-hand side. This is the entire cohort, like every single patient counted their response. You look into those two together with what you're looking into the baseline characteristics before. This is very hard, right? These are very hard results to be seen on the street of the population. I just wanted to make that point because I think it's quite important to put in context that patients are capturing their seizures every single day. When you put this all together and having such a robust reduction here, it's very, very clearly a drug and it's very clearly to risk all the program as we move forward. Maybe to answer your question about the background, we did a few cuts that we thought was interesting to explain that, right? We're seeing this very high response rates. We look into patients without any seizures at the last 28 days. We're like asking the question, okay, what is driving this? What is driving this high? There are a few things that are kind of obvious questions. If we could go to the next slide, it seems like you have the entire deck there. I think the first question one can ask and has been debated a lot in epilepsy is what is the influence of where they start, right? They come into this study, they are treated with a lot of anti-seizure medications. They have this disease oftentimes for decades. They failed tons of other drugs before, and they're seizing a lot. Is the drug working on people who are seizing very little and not working at all on the ones that are seizing a lot at baseline, of course, on the 28 days of baseline, or that is a general impact? I don't think this is very controversial here. There's always a little bit more numerically response on the lower patients, right? Just by definition, I think it's easy to understand. It is a question, right? Like what happens when you split this group in the middle? Now when you find the right, like perfect time points, like it's not like if you pick like eight here and it's like I split the group on that. It's like when you split by the median, it's nice to see they split like being so homogeneous. If you go to the next one, I think that's where it answers part of your questions, actually. One thing a priority we did not expect, Joon, was the amount of patients actually being on stable dose, high dose, right? To give you a little bit of a view, I think when you actually ask a lot of physicians, when you look into the claims data, the dose of cenobamate in the U.S. is normally between 200 mg- 300 mg per day. Very few people go higher than that. Here, the mean was actually 300 mg. You had a significant portion of patients with more than 300 mg, 400 mg, even 450 mg per day. This is a very unique opportunity that we had because no one so far developed like a drug that had a result after cenobamate became so important in the market. We know how effective that drug is, right? Yeah. If you asked me this before, I was like, what is your expectation for how well this is going to work on top of cenobamate? I would probably have said not that high, right? This drug is very effective. There's probably a lot of, there's not a lot of residual like ability to help there. If you flip to the next one, I'm really going to answer your question since I've been lingering here on answering your question. You get the three most common ASMs used here, right? Like sodium channel blockers in general, and that might be two, might be three. Of course, includes cenobamate as well. levetiracetam and Briviact, which is a very prevalent one as well in this cohort, and cenobamate by itself. You see, it's very effective across the boards. One could argue if you're going to remove something a priori, what would you remove? Of course, this is the discussion to be held with the PI and with the doctors. Isn't that an easy question here? Because cenobamate is the riskiest drug. Would you remove cenobamate first? I don't know. Isn't that? I think that is a fairly reasonable way to think about that. As you can see, there are multiple ways, but maybe the most fundamental question is do you actually need to remove something? If you're talking about Power 2, the answer is probably not always or most of the time not yes. When you go to Power 3, yes, we're looking for a switch to monotherapy. We're going to have to reduce things, and it might be an order of the reduction. Got it. Hey, Marcio, before we move on, I just want to better understand. There were some patients who discontinued. These data represent all 37 patients who. That's correct. Were included in the analysis. Now, 23% discontinued, which is not out of the order. We can talk about that. Why don't we actually go there? Yeah. You know, this is a paper from Zenon's publication where in the 25 mg that they're taking forward, 114 were enrolled, of which 26 did not complete for whatever reason. About 23% discontinued. It's not out of the ordinary. They also had to deal with some imputation of data that were missing based on the discontinuations. I don't know. This is what they showed. It kind of looks similar to what you show here in terms of the fluctuations here and there. There's definitely some noise there, but how were the missing data imputed from the patients who discontinued? Yeah, so epilepsy has this interesting. If you read like the statistical analysis plans and the reviews, they say there's no imputation, right? Technically, it's not exactly right because you use the rates of the patients at that given point in time to use as the terminal rates, and that is equivalent to imputing the average. Basically, the way it works is let's say a patient had two weeks and they had whatever, 10 seizures, right? We're going to do like 14 days on that week, 10 seizures, calculate a rate per day, multiply by 28. On that one, it's pretty easy. It's 20. That is basically the rates, and you compare with the previous 28 days. That's how you calculate, and then you carry that forward. I think some people say that's the last observation carried forward. It's really not, right? It's not the last time you observed. It's the overall rates carrying forward. All of that is included. It tends to penalize the median. It does here, as you can see. It's probably the best way to look into the overall impact. What we know from treating physicians, they're not treating the discontinued patients. They're treating the continued patients. There's always an interest on the overall impact, which is what you have in this slide, but also what is the impact in general when I keep treating these patients. Marcio, because, you know, the patients gain the most seizure reduction in the first week or two, as shown here, if you actually have a patient who discontinues at week three or four and you're applying the rate of seizure reduction in week one and two out to week eight or so, wouldn't that actually unfairly favor greater seizure reduction? Yeah, no, I wish, right? What you are seeing here is the median per week. In that given week, who is having the response and the median for that week, not the overall. You have on any given week people who respond really well, people that don't respond so well, right? If those are the ones who drop, as it tends to be, you actually don't influence as much on the weekly base, but you do influence a lot on the final. I get it. It depends on who drops out. Is it fair to assume that people who discontinue are self-selecting in a way? They drop out because it doesn't work as well rather than just not working really well. Yeah. It should have been obvious in the charts, but maybe did a poor job on the scale. There is a fairly substantial reduction between the first periods and the second periods here, right? By being first period, second period is the first month on drug and the second month on drug. In a sense, the worst thing is actually towards the end for a discontinuation to happen. The best thing for the clinical imputation is actually the worst thing towards the beginning. Is it fair to assume that how you analyze the data here in terms of imputation of discontinuation, patient data from discontinued patients are no different than how this? Yeah, it's actually identical. Okay. It's an industry standard. Yeah. Nothing suspicious there. Okay, good. Good to know. The other thing I want to touch on is, let's see. Yeah, I think that we're going to end up spending quite a bit of time here. I definitely want to leave five, 10 minutes at the end for questions and also to go over Power 1 and 2 and 3. You know, 23 patients, 23% discontinued, which again is not out of the ordinary versus the Zenon's trial and cenobamate's trial in hindsight. You also mentioned in the book this, like, you know, discontinuation of reducing the background medication should improve adherence or, you know, how are you going to do this? I I know that maybe you're encouraging investigators to say, you know what? Some of the background medications you don't need or not working, why bother and just clean them up a bit. How is that going to work in Power 1, 2, and 3? In a blinded trial, you know, investigators don't know if the patient is on or not on relutrigine. Would they be more hesitant to peel off the drugs? Fair. No, absolutely fair. A couple of points there even before we jump into the Power 1, 2, and 3 studies, right? You are right. It's like 23% is, I would say, similar in general to what you're seeing in other epilepsy studies. Nothing to be alarmed there. We do think we can do better, right? I think that's why we're talking about that. Do we need to do better? Maybe that's the first question. I think we always have to try to do better for patients, but let's take that aside for a second. The answer is no, right? If that was it, this is going to be a competitive drug. This is going to be a drug that's going to get a very significant market share in a competitive setting and can move towards actually being a dominant player when you remove sodium channel blockers or other drugs in the market. If nothing else, all things being equal, that is totally fine. I think the observation we wanted to give here is because that option was on the table for the investigators. They're like, do you? Some of them took and some didn't, right? We're saying when they did talk that, there are a couple of things that are from a learning perspective. This is a learning study, right? We said from the beginning, we want to learn a number of things. The very first learning is, does the efficacy deteriorate? That is the most important question that I don't get asked in these slides. You reduce the dose of the background. If the background is what was keeping things together for these patients, and I can say quite definitively, no, those patients responded really well. That is like you can entirely attribute that response to relutrigine. That's quite important, right? As we move the drug forwards, then the implementation on Power 1, and it might be a little bit too late on Power 1 for any implementation. We'll talk about that in a second. It doesn't seem to be needed either, right? A couple of things that from a Power 1 perspective, like going pretty well. We're not done yet, but we're pretty happy with where we are. What you've seen so far, if we use like the worst case for placebo, meaning no one discontinued, and or the best case, and the worst case for a drug and like the majority, we're not seeing the levels of discontinuation we're seeing here. I think we feel that even the training that was reimplemented and really the counseling of the patients and a lot of that was sufficient to minimize some of those because the majority of the AEs were really fairly quick, transient, mild in nature. Is that a big deal when we have, like again, in the grand scheme of things, a fairly low, and I know 59% does not look low, but it's comparatively fairly low treatment-emerging AEs, and we can actually manage. I don't think that we are in a territory that it is an issue here. We are starting with this is not a problem, and then we are moving to can we make it better? I think that that's quite important as we discuss these aspects, right? We're trying to make a problem out of something that is not a problem, maybe because we said we can do better, but our intent is always to do better. That's why we spend time here. What percentage of the 23% discontinuation was due to AEs or some other reason? Yeah, we were very good about following up with the patients and with the investigators and understanding was there an AE associated with, right? One could argue to all faults because when patients discontinue and you go and ask them afterwards, they're like, I wanted to discontinue, and you record that as patient choice. You avoid the terminology of the AE, but if you say you had an AE, you discontinue. You normally record the AE. The vast majority of the patients said, I had an AE and I discontinued. That's what I believe happens in most of these studies, and that's the case here. I mean, I guess you did some of the work for us in comparing drugs. A little bit. I mean, look, 59% or 52% PAE drug-related, it doesn't look all that bad relative to other drugs. I'm going to take an issue with that. If 30% or 40% less patients are having treatment-emerging AEs, that is a lot better. We can talk about being comparatively everywhere else, but I'll take a problem here because it's not only the rates when they have it, that's how AEs sometimes are calculated, but are they having treatment-emerging AEs at all? 60 versus 90 versus 85 are very different numbers. You're talking about a significant proportion of patients not experiencing treatment-emerging. For the vision of the drug, for the get-to-the-market, be competitive, get a good share might not be so important, but in the long run, it is quite important for where we want this drug to be. When you unveiled the plans for Power 3 yesterday for the first time, in an effort to study relutrigine as a standalone or monotherapy, right? Same thing, standalone monotherapy, where they get washed out of the background therapy. People thought you could have a bearish and a bullish interpretation of this, right? The bullish is that you want to study this as a monotherapy, potentially positioning it as a more frontline therapy ahead of other sodium channel blockers. The bearish argument is that there must be some drug-drug interaction that you're trying to avoid as a monotherapy. When did you figure out, when did you decide on the Power 3? Tell us a little bit of the history and conversations that went on with the investigators and internally in the decision to do Power 3. Yeah, I love the conspiracy theories, right? In the end slides, that is like the GGI profile for all these drugs. By the way, we combine the drug with all these others. Like that, no one's trying to avoid the GGI here on the very concept of GGI. That has nothing to do with that. I move into what it has to do with, right? If you think about the markets, I'll go back to the market with epilepsy, right? Getting off the gates, we're going to add another drug for refractory patients, right? Power 1 and Power 2 are going to position us to do that. The market is $1 billion to $2 billion. If there are five other drugs, they're all going to be $1 billion- $2 billion. That is not a winner-take-all market, right? That is like markets that people cycle, there are several patients there. One could argue that is enough and sufficient and great and a win to actually be in a position to de-risk that position. When you take a step back and ask like where does this drug can go, then we believe strongly that it can keep moving lower in the adoption curve. The best way to show that is to actually remove some of those drugs. Now, do we need to remove it? I think we answered that before as a no, as a condition to be successful in the market. Should we remove it or should we test it and make sure we can remove it so we can move faster towards first line and then actually replace all the drugs that they shouldn't be in eventually and have a market that hopefully at one point is going to be two or three drugs that are used in general instead of like this, in a sense, madness that happens with all these drugs right now. This is a conversion to monotherapy, right? Or patients got reduced sequentially. To answer your question, what do you take first? They're going to be one or two. You can choose the one or the two, and you're going to take a dent. You're going to introduce relutrigine at the same time for these patients with the expectation that they're not going to lose ground and they're going to gain response. Many studies like this were done before. I think some of them are fairly old and some of them use like subclinical dose of other drugs. I think those are all deemed to be unethical to be run because like we're using subclinical dose for other therapies and things like that. Some of them use like escape rates during that conversion and so on. I think we're all still having some debates on how to do it. I think our strong preference is really to try to keep these patients as stable as possible, of course, as safe as possible. Some of those escape rates in the past were very aggressive, not towards the patient. Like 2 or 3x increase in seizures, you don't think that that's fair to patients at this day and age. We're going to get back to the design of this once we finalize. We're going to start this next year. Maybe the other part to be excited is actually the Power 2, 1, that we are starting clinical now by the end of this quarter, where we had a key question for Radiens. Going back to the things that we intended to answer with Radiens, right? Was 30 mg an effective dose? Can we dose that off the gates without any titration, without any adjustments there? I think we checked those boxes, right? Should all agree we checked those boxes. Then a secondary question there was, do we have reasonable evidence that if we give more drug on board, that the efficacy could be better? One, from a response rate perspective versus exposure. On the other side, is the side effect profile worse if we increase the drug? If they are, then you got to be very careful. If they're not, if the efficacy is higher and the side effect profile is equal or lower, then you know it's almost you have to go there. You have a base, quite strong, solid foundation with the 30, but you can explore these new heights with the 40. That's how we picked the 40 here. Basically, just got the rationale for you there. On Power 2, we can more aggressively, I'll call the word aggressively, not with aggression, but with being incisive here to reduce the drug, the background drugs by a bit, by 20% or so in the first week. Our levels are fairly safe, but can actually keep all these patients responding better and managing them better. That answers your other question, how do you manage on Power 2? Power 1, too late, but we're pretty confident that all the measures already in place were able to manage. We'll be able to, we're able to manage. I think in Power 2, it's going to be even more effective. Going back to Power 1, what's the, I got a lot of questions around the timing of Power 1. In some slide, you say you will finalize the Power 1 in 4Q. In other slides, I think you said you'll report in the second half of the year. What's the status there? Yeah, so it's last mile for Power 1, right? When you're in the last mile of something, you always start asking the questions like, okay, when does it end to get like the actual race? You get marked up the time, and that's when last patient, last visits. When do you get the medal? That requires a lot of other stuff to happen. When you look into that, it is the end of the year. Being the end of the year, we thought it was prudent to just give that end of the year view right now. That's the disclosure we have right now. I know there were some conspiracy theories about that as well. There is nothing there. It's just a fast-moving study. Every fast-moving study has thousands of pieces that are moving. We're very confident. We're very happy with the number of cases that are being referred every single day to sites. On the medical review, on the quality of the patients, on everything else, just like we were on Radiens. Here we go. Not only did we run the 35+ that we said we would, but many more there. Almost every single patient between 35 and the 60 you're seeing in Radiens would qualify for Power 1. We got to ask the question, we got to be fairly confident to be able to keep them on Radiens when you actually didn't need that instead of actually funneling them to Power 1. It's fair to assume that the baseline characteristics in Power 1 will be very similar to what we saw in Radiens? Very, very similar, yes. Right. The last question before I read some of the investor questions, IEC on August 31st, what do you think you'll be, what are you going to share or to the extent that you can share, what will it be? Yeah, we'll tell a little bit. Of course, a little bit more about everything we talked today. That's obviously a scientific meeting. There is a lot more, a little bit of the details here and there. We do have a few new analyses that we conducted. For example, one that we're very excited about is by seizure type. Really showing that, as you know, there are four major seizure types that we actually measure as we go through. Three of them get part of the endpoint. One of them is normally not part of the endpoints. Really showing that, I think, is quite interesting. It's quite interesting in general, but it's incredibly interesting from the impact you're having, like is that across the board, is that a seizure type? What about the ones that are like focal to bilateral, right? Generalized type of seizures. Without giving too much on saying we're excited about that as well. A few other things here and there. Of course, we need to be careful scientifically and otherwise where IEC had a purpose. AES has a different one. We submitted the full or the expectation to have the full data sets to AES over the weekend. That's where we expect to be the entire wrap-up for all the patients. All right. I don't even know where to start with the questions. What evidence do you have that going to 40 mg is going to lead to better efficacy? What kind of internal, you know, what exposure data do you have that supports going to 40 mg? Yeah. So again, going back several months ago when people asked why are we doing Radiens, one thing we said is conducting intense PK sampling is easier in a study that you know patients are on drug. It's easier to ask for a patient to stay like a full day taking samples than in a double-blind study. That was one. With that, we can not only understand better the PK of the drug itself in patients, not in healthy volunteers. Second, we can use that data to fit to a PK modeling, to do a lot of exposure response, to explore covariant matrices, and things like that. Starting with the first one, the very first question, is the exposure different, right, in healthy volunteers and in patients with epilepsy? It answers indirectly your question on is there a significant GDI hidden here in planned sites that we actually haven't detected that is influencing the PK of this drug? I can tell you quite categorically, the answer is no. The exposures are very, very comparable between healthy volunteers. That is very important. Very important because, of course, we know the drug's behaving well. Second is we have safety on 45 in healthy volunteers. We can borrow that experience to predict safety, as you said about Power 2 and how we select that. The second question is the one I answered before, but just to reiterate, when you actually use now the exposure response parts of this modeling, and you ask the question, are higher exposures? I would say preliminarily, because for people familiar with these models that it takes a while for them to be finalized, preliminarily, I can say that is low risk is positive, right? Meaning you give more drug, you see more response for some patients. It's not something exaggerated. It's not something bimodal where you see like no response and then high response. There are some hints there that we could benefit, number one, and you're not harming, number two, which is quite important. When you put that all together, and the fact that the FDA told us they would kind of like for us to explore a higher dose, I think that seals the deal. You had a pre-Phase III meeting with the FDA, and you brought up the Power 2 dosing up to 40, and they were okay? Yeah, so we had an interaction with the agency where we basically exposed the entire program. We were like, this is what we're trying to accomplish here with this drug, right? Power 1, Power 2, Radiens from exposure, DDI, like phase I studies, you name it. I think the feedback at that point in time, we were under the impression that they would want us to go lower to like 10 mg. If you go back to previous disclosure, you even added that 10 mg. Like we're so convinced they're going to tell us to go there. They're like, well, maybe we should go there. I think the feedback was quite different. They're like, look, if you really believe on the profile of the drug you're describing to us, right, it might be warranted to actually go higher. I think we took that to heart. Here we are on a point that all scientific boxes are checked towards going to 40 mg because we can expect potentially, of course, we need to run the experiments, like a higher yet than like Power 1 should be very solid. We expect Power 1 to be very solid efficacy and safety. If Power 2 replicates that efficacy on the 20 and 30 mg and actually gets higher on 40 mg, it gives a lot of flexibility for physicians to use this drug on how to treat their patients. There were, on average, two background medications and ASMs. How many, is there data on how many they failed? Yeah, very substantial number of ASMs they failed. I would say the worst case here was 22 or 23 ASMs. Patients in general, like five, six, seven, ten was not uncommon on this data set. In general, we'd see four or five ASMs being failed throughout. That is even the ones that I would argue the patients recall and the physicians have on their records. You tend to have a limit for like 10 years of medical records in most patients in the U.S. The majority of the patients have more than 10 years of epilepsy treatment. Got it. Yeah. Someone's asking, you mentioned something about the interim dropout rate in Power 1 being lower than that in Radiens. What does it look like on a blind patient so far in terms of dropouts and discontinuations in Power 1? Always tricky to talk about ongoing studies. Please take with a grain of salt. I think what we are seeing so far is lower, and it can be for many reasons, right? It's hard to speculate. I think one of them is if for an open-label study as Radiens was or is, I guess, too ongoing for those other patients, you have something like have a headache, I'm going to call, you attribute immediately to the drug, and you're like, I'm not sure I want to stay with this. I think when you are in a double-blind study and you have headaches before and dizziness before and somnolence before because these patients live with all these other drugs, it's not so easily attributable. That might be one. I think the other one is there were somewhat of a relationship with a few sites where they have higher dropout rates than others. It so happens that they were not sites that had a lot more patients to offer to clinical studies. They are not really contributing as much or contributed as much for Power 1 proportionately, which allows for actually the sites who didn't have any, who had bigger to be a bigger contributor. The last one is training, right? It's just like going back and on the counseling, on the ICF, and everything else being better. I can't possibly disentangle which one of those parameters actually is influencing the most, but certainly all of them are. How many of the 37 patients actually had their background ASMs reduced? Six of those patients had their background reduced. None of them got completely removed during the eight weeks period, which is a question I got as well the other day or yesterday. It was a reduction. The majority of the time was like 30%- 50% the reduction they had. That was completely investigator-driven, right? They would think it's a good idea and they would reduce it. Okay. Let me see. I mean, there's so many questions. Gosh. Pick the tough ones. Somebody's asking, should we still expect essential tremor update in the fall? Oh gosh, okay. You really meant to pick a tough one. We just updated the disclosure yesterday to talk about, like, we finalized since we went there and seeing if there is some general interest. I always start by saying we ask everyone not to attribute any value to essential tremor right now, to take it out of their models. Having said that, we have completed all the explorations we wanted to complete in all the modeling and so on, on the blinded data for study one and study two. We believe that we found, like, some small change that would quite significantly impact the result of the analysis, but not the integrity of the analysis, which is always what we are aiming for here. We've made those changes to the statistical analysis plan. In the process of doing that, we enrolled a few more patients. We wanted to get the studies to rolling before we actually finalize the documents. That's all said and done. In the past, we said the fall because it's really like the kind of the very end of September to, like, the beginning of October. Someone joked with me yesterday, it goes all the way to November. Is that what you're talking about? I'm like, no, that's not what we're talking about. It's really that interface between the end of September, beginning of October. Great. Do you know if Zenon's trial allowed cenobamate as a background therapy or not? Yeah, it's very unclear. I think by the public protocols, I believe so. I would imagine so. It would be interesting, if not in the most American way I can say the word interesting. I would imagine cenobamate prescriptions grew about 12, 13-fold since the last study was conducted by then. That is a lot of those sites that you end up going to have a lot of cenobamate to use, as you've seen was over 30% in our studies. I would imagine it's the same on theirs and anyone else's studies. I think we're past the hour, and we asked a lot of questions. The questions keep coming in. Maybe I can ask this one last question. What was the seizure free rate in the first 28 days? Yeah. The seizure free, and of course this is stuff that we are holding for IEC and AES, but I'll give a little hint, right? The seizure free rate throughout the study, both first 20, entire study, last 20, was all high double digits. There is nothing weird here. Seizure freedom rate. Yes. Interesting. All right. You know, the questions that keep coming in, but I think we can also do another one of these. It's very interesting data. I think seizure freedom rate, efficacy on top of sodium channel blockers, multiple sometimes, says a lot about the drug's profile. It's just about designing a trial design that shows the true power of this relutrigine. We look forward to the presentations on August 31 and further disclosures in 4Q. Likewise, thank you so much for the time. Absolutely. Thanks everyone for joining. Take care. Bye-bye.