Good morning, everybody. I'm Doug Tsao, Senior Analyst at H.C. Wainwright. Thanks for joining us for -- what I'm calling a special edition of my call series, which usually runs in the spring. We did have Marcio and Tim with us then. Just given some recent events, I thought it would be worthwhile for us to get together. You know, I certainly, you know, before we jump in, I would say that the, what you know, I'd call the re-rating of Praxis has opened the story to a much broader investor universe. I think it's a good opportunity to sort of cover some of the hot topics that have developed. Obviously, you know, Ulixacaltamide and the successful phase III is a topic, although I think we're going to start with Relutrigine because I personally have felt that this was an asset that was being significantly overlooked by the street and certainly justified, and even I would argue today could justify the company's valuation. You know, we'll start there. Marcio, you know, you've been hinting at for some time about an accelerated pathway, and notably saying that, you know, the PRV was still in play, which if we had sort of run out the timelines of when things were going to get filed and the likelihood of, you know, that potentially that program expiring next September, you know, kind of probably fostered some questions or people sort of were not sure how that how we were going to get there, so to speak. Yeah. You know, and so obviously now it seems that that is very much in play. And, you know, but just given where you are as a company, I would argue you know the $100 million-$150 million is maybe not as meaningful. And I'm much more interested in just getting to market, you know, that early. But maybe just provide some background on how things evolved from the initial readout of the first cohort of EMBOLD to getting Breakthrough Therapy Designation, and then finally, you know, getting alignment with the agency on this interim analysis. Yeah, absolutely. I like the way you position that, where we still believe, right, that it's not as appreciated as it could be. I also think that is going to get there. Like time cures most things. The story is actually very, very similar to one we're going to talk about, Ulixa, to be honest, Doug. Like we're going to fields here, particularly on SCN2A and SCN8A, where there is really no drug that has ever been developed. Right? When we've done the first cohort for EMBOLD, the question that we're asking is like, how, like, is the effect, does the effect exist that we expect for this drug, for Relutrigine number one? Two, is this design that we put together, taking into consideration the patient needs and so on, robust enough to not only show that design, but be accepted by the regulators? We answered those questions on the first part, like we've seen like very robust effects, like it was very successful from a design perspective. We put that in front of the FDA, we got Breakthrough Designation based on that and on the long-term extension of that study. At the time, you might recall we have the readouts. We said we're not going to stop, we're going to create a new cohort that is basically an image of the first cohort with one change, right, with the dose being higher on this cohort than it was originally. We're going to run these registrational cohorts. We expected at that point in time that the need for a safety database was like, I would say a more traditional run around 100 or so patients. That's how we started. We obviously stayed in dialogue with the agency, but particularly after being granted Breakthrough Designation. On that dialogue, we could check a lot of boxes, a lot of things that we had questions. But there was an invitation, I would call it that way, by the agency to think about how to accelerate this. There are a number of ways to accelerate a program. I think the most maybe, I'm going to call aggressive, but I don't mean this negatively, but the most aggressive one would be go with the initial cohorts, like and make the case that those 15 patients would constitute substantial evidence of effectiveness, like the data is clear, it's robust, and so on. We actually did not think that that was a winning proposition, right? Maybe the agents would say, okay, file, but we did not want to end up in a situation that is just a half check the box. I think the other was potential for combining with different things, and we did not think that was appropriate either. What was clear is that we did not really need, quote unquote, from a power perspective, all 80 patients, right, that were originally designed. That opened a dialogue when saying, what is the number that we feel very comfortable and that maximizes the protocol success, which is a shared interest between us and the agency. At the same time, bring this drug to a patient population that does not really have a good alternative right now. We end up with this, what I am going to call front-loaded interim, right, because we are using most of the alpha at the interim. In a large enough cohort that the chance of success is very high. It would allow us not only to declare this study successful this quarter, if that's what happens, but also to submit an NDA very quickly and therefore get the unmet need fulfilled fairly quickly there as well. It brings two other benefits. That is obviously great. It's going to be great for the company, for the patients, and so on. There are two other benefits here. One is the Pediatric Review Voucher that you said is still now more than ever possible. While I partially agree with you that it's less important, I think non-dilutive capital is always very important for the company, so I'll appreciate that. The second is it brings the first NDA approval earlier, and therefore the second that would be on the base of EMERALD, that is the very large population, like it shortens that timeline. When you think about a total market opportunity perspective, we are accelerating that multi-billion dollar opportunity way earlier. Not only the smaller, but quite meaningful as well opportunity with the SCN2A and 8A. It was very clearly a win-win without any compromise, without having to have any uncomfortable discussions with the agents as well in terms of things that they're not quite ready, like external controls or things like that. We're really talking about a prospectively controlled study with placebo. It's a little bit, yeah, the design is a little bit different than your parallel group design several weeks, but the concept is nuts, right? The concept is very clear. It's very well understood by the agents and they very much welcome that as well. Sorry for the long answer to the rather simple question, but I thought it was important. No, no. I guess maybe just to clarify, will you provide exactly what you mean by bringing forward the opportunity for the EMERALD population, right, the broader DEE population, and the sort of steps that this. [audio distortion] Yeah. The strategy for EMERALD was always to have the first NDA within EMBOLD. With that approval, we can submit for an sNDA, right? Having that, for the latest, if the first becomes delayed, the other one becomes delayed as well. We always expected, and we still do, to finalize EMERALDs in the process of review or around the approval of what is now the timelines we're discussing about in EMBOLD. In a sense, the EMBOLD NDA would be the rate limiting now to the EMERALD approval, or what I'm calling EMERALD, but you know what I mean, right? It's the larger DEE population. Accelerating that is not only 2A and 8A, that's what I'm trying to say. You accelerate the entire area under the curve, right? You shift to the rights in terms of the overall opportunity, quite meaningfully, right? Anywhere between six months and a year and a multi-billion dollar opportunity is very, very meaningful for all of us and obviously patients particularly. Okay. I think I'm going to come back to EMERALD later, but I don't want to go too far down that rabbit hole, although I don't think rabbit hole is the right way to put it, but you know, go down that path. You know, with the announcement earlier this week, you did update the data from the first cohort to provide a P value, right? I guess you went from the prior data that you had reported, which was just basically, I think, the comparison of seizure reductions to sort of the log scale difference. I think one of the things that was noteworthy to me was how small the P value really was. I think you've said that this is basically the same model, right, that you're going to be using for the interim analysis, which I think you said is an ANCOVA. I guess just for those who want to get into the weeds, maybe provide some perspectives on sort of what the variables that you'll be using in this ANCOVA model and sort of controlling for. Also, you know, you have such a unique design in that in the placebo arm, right? Patients do have this crossover. Yeah. Patients do have, right, you know, they had this, do have this four-week placebo period, but they also have 12 weeks of drug therapy, right? I guess we do not exactly know which group is that, you know, when that placebo period is. Maybe if you could just help us understand from a stats standpoint, you know, what the terms are, the variables are, or the covariates are in this. Yeah, absolutely. This is exactly what, in a sense, what you just said, right? We agree on a way to analyze the data with the agency, one that understands basically the structure of the data and just how skewed one could call the baseline is on patients like this. We agree on that. Because the agreement is, I would say, slightly different than how we presented the first cohort, right? We just showed like a sample median comparison originally. We thought it would be appropriate to actually say, if we just look into the cohorts the same way we're looking to now for to declare success. Good morning, everybody. I'm Doug Tsao, Senior Analyst at H.C. Wainwright. Thanks for joining us for -- what I'm calling a special edition of my call series, which usually runs in the spring. And we did have Marcio and Tim with us then, but just given some recent events, I thought it would be worthwhile for us to get together. You know, I certainly, you know, before we jump in, I would say that the, what you know, I'd call the re-rating of Praxis has opened the story to a much broader investor universe. And so I think it's a good opportunity to sort of cover some of the hot topics that of things that have developed. Obviously, you know, Ulixacaltamide and the successful phase III is a topic, although I think we're going to start with Relutrigine because I personally have felt that this was an asset that was being significantly overlooked by the street and certainly justified, and even I would argue today could justify the company's valuation. You know, we'll start there. And Marcio, you know, you've been hinting at for some time about an accelerated pathway and notably saying that, you know, the PRV was still in play, which if we had sort of run out the timelines of when things were going to get filed and the likelihood of, you know, that potentially that program expiring next September, you know, kind of probably fostered some questions or people sort of were not sure how we were going to get there, so to speak. Yeah. You know, and so obviously now it seems that that is very much in play. You know, but just given where you are as a company, I would argue, you know, the $100 million-$150 million is maybe not as meaningful. I'm much more interested in just getting to market, you know, that early. Maybe just provide some background on how things evolved from the initial readout of the first cohort of EMBOLD to getting Breakthrough Therapy Designation and then finally, you know, getting alignment with the agency on this interim analysis. Yeah, yeah, absolutely. I like the way you position that. We still believe, right, that it's not as appreciated as it could be. I also think that is going to get there. Like time cures most things. The story is actually very, very similar to one we're going to talk about, Ulixa, to be honest, Doug. Like we're going to field here, particularly on SCN2A and SCN8A, where there is really no drug that ever been developed, right? So when we've done the first cohort for EMBOLD, the question that we're asking is like, how, like is the effect, does the effect exist that we expect for this drug for Relutrigine number one? And two, is this design that we put together, taking into consideration the patient needs and so on, robust enough to not only show that design, but be accepted by the regulators? We answered those questions on the first part, like we've seen like very robust effects, like it was very successful from a design perspective. We put that in front of the FDA, we got Breakthrough Designation based on that and on the long-term extension of that study. At the time, you might recall we have the readouts. We said we're not going to stop, we're going to create a new cohort that is basically an image of the first cohort with one change, right, with the dose being higher on this cohort than it was originally. We're going to run this registrational cohort. We expected at that point in time that the need for a safety database was like, I would say a more traditional run around 100 or so patients. That's how we started. We obviously stayed in dialogue with the agency, but particularly after being granted Breakthrough Designation. On that dialogue, we could check a lot of boxes, a lot of things that we had questions. That was an invitation, I would call that way by the agency to think about how to accelerate this. There are a number of ways to accelerate a program. I think the most maybe, I'm going to call aggressive, but I do not mean this negatively, but the most aggressive one would be go with the initial cohorts, like and make the case that those 15 patients would constitute substantial evidence of effectiveness, like the data is clear, it is robust, and so on. We actually did not think that that was a winning proposition, right? Maybe the agents would say, okay, file, but we didn't want to end up in a situation that is just a half check the box. I think the other was potential for combining with different things, and we didn't think that was appropriate either. What was clear is that we didn't really need, quote unquote, from a power perspective, all 80 patients, right, that were originally designed. That opened a dialogue when saying, what is the number that we feel very comfortable and that maximize the protocol success, which is a shared interest between us and the agency. At the same time, bring this drug to a patient population that don't really have a good alternative right now. We end up with this, what I'm going to call front-loaded entrant, right, because we're using most of the alpha at the entrant, but in a large enough cohort that the chance of success is very high. It would allow us not only to declare this study successful this quarter, if that's what happens, but also like to submit an NDA very quickly and therefore get the unmet need fulfilled fairly quickly there as well. It brings two other benefits, right? That is obviously great. It's going to be great for the company, for the patients, and so on. There are two other benefits here. One is the Pediatric Review Voucher that you said that is still now more than ever possible. While I partially agree with you that it's less important, I think non-dilutive capital is always very important for the company, so I'll appreciate that. The second is it brings the first NDA approval earlier and therefore the second that would be on the base of EMERALD, that is the very large population, like it shortens that timeline. When you think about a total market opportunity perspective, we are accelerating that multi-billion dollar opportunity way earlier, not only the smaller, but quite meaningful as well opportunity with the SCN2A and 8A. It was very clearly a win-win without any compromise, without having to have any uncomfortable discussions with the agents as well in terms of things that they're not quite ready, like external controls or things like that. We're really talking about a prospectively controlled study with placebo. It's a little bit, yeah, the design is a little bit different than your parallel group design several weeks, but it is the concept is not, right? The concept is very clear. It's very well understood by the agents and they very much welcome that as well. Sorry for the long answer to the rather simple question, but I thought it was important. No, no. I guess maybe just to clarify or provide exactly what you mean by bringing forward the opportunity for the EMERALD population, right? The broader DEE population and the sort of steps that this. Yeah. So the strategy for EMERALD was always to have the first NDA within EMBOLD. And then with that approval, we can submit for an sNDA, right? And then having that. For the latest, it is the first, it becomes the other one becomes delayed as well. We always expected and we still do to finalize EMERALDs in the process of review or around the approval of what is now the timelines we're discussing about in EMBOLD. In a sense, the EMBOLD NDA would be the rate limiting now to the EMERALD approval or what I'm calling EMERALD, but you know what I mean, right? It's the larger DEE population. Accelerating that is not only 2A and 8A, that's what I'm trying to say. You accelerate the entire area under the curve, right? You shift to the rights in terms of the overall opportunity quite meaningfully, right? Anywhere between six months and a year in a multi-billion dollar opportunity is very, very meaningful for all of us and obviously patients particularly. Okay. And I think I'm going to come back to EMERALD later, but I don't want to go too far down that rabbit hole, although I don't think rabbit hole is the right way to put it, but you know, go down that path. You know, with the announcement earlier this week, you did update the data from the first cohort to provide a P value, right? And I guess you went from the prior data that you had reported, which was just basically, I think the comparison of seizure reductions to sort of the log scale difference. And I think one of the things that was noteworthy to me was how small the P value really was. And I think you've said that this is basically the same model, right, that you're going to be using for the interim analysis, which I think you said is an ANCOVA. I guess just for those who want to get into the weeds, maybe provide some perspectives on sort of what the variables that you'll be using in this ANCOVA model and sort of controlling for. Also, you know, you have such a unique design in that in the placebo arm, right? Patients do have this crossover. Yeah. Patients do have, right, you know, they had this, do have this four-week placebo period, but they also have 12 weeks of drug therapy, right? I guess we do not exactly know which group is that, you know, when that placebo period is. Maybe if you could just help us understand from a stats standpoint, you know, what the terms are, the variables are that or the covariates are in this. Yeah, absolutely. This is exactly what, in a sense, what you just said, right? We agree on a way to analyze the data with the agency, one that understands basically the structure of the data and just how skewed one could call the baseline is on patients like this. We agree on that. Because the agreement is, I would say, slightly different than how we presented the first cohort, right? We just showed like a sample medians comparison originally. We thought it would be appropriate to actually say, if we just look into the cohorts the same way we're looking to now for to declare success, how does that look? How does that compare? Which we thought was an appropriate question. That is what the comparison is for, right? To your point, that is a reason why we did not show those p-values before. It is like that was not the question we are asking of that cohort, right? We are not asking, is this like significant to the 5% alpha level, yada, yada, yada. We are asking the questions like, how do you design these next cohorts, right? Now, it becomes important now because this interim is not at full, it is not at 100% of the patients. I would imagine if I am sitting on your shoes, on the investor's shoes, it is the question of like, how risky is this? You need to have a place to anchor the risk. That is why we showed the p-value and the difference there. If you fast forward and you try to simulate status, I am sure some of you are, you see, you actually need an even smaller study. I'm going to leave it like that right now. What one can say is it's exactly the same model that we're using with the final. It's one that the agents, we're very explicit on what we're using. We have very explicit agreements with them on the way that this is being calculated, which is obviously the way it should always be. This day and age, I think it's important to say it. Marcio, can you confirm that sort of baseline seizure counts is the sort of primary covariate that you're adjusting for? Because I presume there's a pretty wide spread and distribution for patients. Yes, yes, of course, you'd want the log transformation to be used as the continuous, right? Yes, that's what it is. Okay. You're asking, you know, as we noted, you're committing a lot of your alpha spend on the interim analysis. Can you walk through what you saw in the first cohort data that made you comfortable with the 70% patients completing? What went into the sizing of EMBOLD originally? What made you think 70% was the right way to do things? Yeah, there's nothing magical about 70%. It could be actually earlier than that, meaning a smaller number than that. There is a very high degree of comfort with 70% or about 60% patients on that when you consider the effective thing before, number one. Obviously, when we discount the effective thing before, because we can't just expect to replicate equally like the other cohorts. The original was, as I mentioned a few minutes back, actually more, and we've been very consistent about this, right? If you go back to conversations we had throughout the last several months, we said we don't actually need 80% for efficacy, but we think that's the appropriate size for safety in case there's a question about the safety database. This was always meant to be the single study leading to approval. We're not developing the drug just to get Wall Street milestones or developing this drug to get approval at the end. We need to think about both benefit and risk and how you make that argument for the agency. At the moment, there was a very clear alignment with the agents that we do not actually need that many patients for the safety database. The equation changed. It becomes how many patients do we need to show efficacy since the safety has been pretty clean so far as we know in this program. That was the rationale there. It could have been less, but it is very well powered at 70%. That's why we were so comfortable in front-loading the alpha at 4%. If we were to think that we get replication of the first cohort data, is it safe to assume that the power is above 90%? Yes. Okay. How do we think about the fact that some patients in the study will get 16 weeks of treatment and others will only get 12 weeks? I guess part of the question is, because if we looked at the extension data from the first cohort, right, patients continue to improve, right, over time. In fact, actually quite dramatically. Fully, yeah. You know, when you think about that dynamic, you know, did you have conversations with the agency? Do you think that this ultimately means that the second cohort will potentially understate the efficacy? Do you think about sort of adding to the label potentially over time with longer data? Yeah. So going back, of course, they've seen all the data that we have so far, including the extension from the first cohort, right? It's part of the overall benefit risk of the drug. When you think about labeling the situation, it's a lot different than in other situations, right? What are physicians being able to prescribe to patients right now? There's no label for any drug. They're just trying to help these patients with something. So understanding the drug effects or any means possible is way more important than what is originally in a label here. I'm not trying to minimize label tax for prescribing information in the U.S. I'm just saying, like, what are you comparing with, right? Comparing to zero, that there's no information. There's only risk in a sense for this patient with other drugs right now. Are we underestimating? I actually would argue that a drug that shows over 20% reduction when patients are on three, two, four anti-seizure medications and they cannot control anything in the first month, as we have seen before, should already be sufficient to get it across the line. Let alone what we see later in the treatment. Now we are very comfortable when we test this target product profile with physicians. I think we have a lot of, like, please get this drug in the market as soon as possible. Maybe part of the motivation by the agency, although I do not know this for a fact, is the amount of requests they get for use of this drug, either through emergency or individual INDs because patients do not qualify necessarily for this study. That is an acute understanding of how much this drug is needed. Of course, if we succeed, always important to have successful drugs like to be given to patients. I mean, but in the, and not to dwell on this point too much, but Marcio, but going back to the data that we got for cohort 1, right, that you gave us, you know, on the same statistical analysis, how do you sort of homogenize that, you know, in theory, this study will have 12, some patients will have 12 weeks data versus others will have 16? Yeah, that is an advantage actually to the design. We kept the design very close to the vest, as you know. We're going to continue to do that all the way to the end of this study because it's fundamental for the integrity of this study that no one guessed. I can tell you, it only helps the way it was designed from the statistical standpoint and from the effects standpoints. I mean through estimation of effect and then statistical power on the other side. I can tell you that the agency understands exactly what the design is. There is no doubt about it. In terms of, you know, sort of coming back to that, that would be a component of the ANCOVA model to address the somewhat differences. I mean, can you sort of give us what the model is? No. If I give you what it is, then I'll tell you a lot more than I actually would be able to say at this point in time. We can't ever risk study integrity, right? It's just to satisfy curiosity. You're going to know soon enough. It is Q4, right? You know that. We're going to read this out in Q4. Marcio, along those lines, if we get a positive readout sometime either this month or next month, would you be in position to file the NDA in January? And where are you from doing things like CMC and the other components for a filing? Yeah. In the scenario you described, right? Without making any like hard looking statements or any promise here, but playing on the scenario you just said, that would be nothing precluding us from filing that NDA very early in the year. You know, one thing that sort of has come up in recent weeks, right, is, you know, the FDA has sort of rolled out the Commissioner's National Priority Vouchers. You know, you have Breakthrough Designation. You know, is that something that you would think might be valuable? As a company, though, are you prepared to potentially, right, accelerate things even that much further, right? You know, because I know companies that have gotten the CNPV who sort of all of a sudden are sort of like, oh my goodness, we're actually going to, you know, we thought we were launching a product at one point, and now we're doing it seven months earlier. Yeah. No, you would welcome that dialogue for sure. That opportunity, like, of course, it's a little bit unclear, as we know, like how those designations/vouchers are being granted. In the case, let's say we believe that that would be something important for us and it would be possible and it would be blessed with being granted, then yes, we would be ready to provide to patients as well. You know, how do you think people sort of getting up to speed with Relutrigine and the EMERALD data, you know, how should they interpret that as it applies to the EMERALD trial, right? You know, in broader DEEs. I know at one point, I think you had said you were not as focused on Dravet, but then you sort of changed course. Maybe if you could provide some perspective on what led you to think that the drug could be effective in that population. Yeah. I think what we're saying, right, for EMERALD, it's not that we are still not as focused on Dravet. We think that the amount needing Dravet is, in a relative scale, a lot smaller than it is in other DEEs. Right? I'm saying relative scale because I'm not trying to minimize the residual amount need on that condition. There are multiple drugs approved. There are multiple drugs in development for Dravet syndrome and for virtually all the other DEEs, there is nothing, right? We're not focusing on that. We can't ignore the science either. When you look into the science for this drug, particularly for Relutrigine, it's very clear and we show that, right, preclinically and hopefully soon shown clinically that there could be additional benefits for those patients. I'm not talking about the 10% or so of what we call Dravet patients that actually gain a function on the SCN1A gene. That is not even something that I normally see coming up, which is a fairly reasonable size of that population. I'm talking about the more classical loss of function 1A or associated disorders there. We've seen that quite exquisitely. There are multiple now publications. I think it's hard when people hear a story throughout their lives to just go back and actually look into the evidence because they believed on their story for so long. Why bother with data, right? The data is actually very clear that the problem is not blocking sodium channels. The problem is how you block it, the sodium channels. The current generation of drugs are just not good enough for those patients. One must admit when faced with evidence that they might have a misconcept. That is why we are going there. Again, it is not a focus. In a sense, it is not a focus at all of EMERALD. EMERALD is going really, really well. We are seeing a very diverse cohort of patients coming in, very clearly with high counts of motor seizures, that is what we are looking for here. We are very excited about it. We are very excited about finalizing that study next year and filing a potential NDA, sNDA right after that, ahead of anyone else developing a broad indication, by the way, for DEEs. That should not go unnoticed there. I mean, to put a finer point to that, I mean, I think you have said that you expect to complete enrollment in the second half of next year. You know, how is that tracking? We have heard about competitor studies moving more slowly. If you were going so fast, what are you doing different? You know, at what point after, you know, would you be positioned to file the sNDA, you know, if we assume that things go well with the SCN2A and 8A populations? Yeah. On the current pace that we have EMERALD going, we should be in a position to file that sNDA. Of course, everything has to work as expected by early 2027. I guess, you know, given the pace of what you're doing in terms of enrollment, what do you think is sort of your secret sauce? I mean, we've seen that to some extent with the power studies, right? You're going much faster than competitors. Can you speak to what you're seeing on the ground relative to other DEEs, which, you know, there's a fair amount of activity? Yeah. Those competitors are. [crosstalk] Yeah. There is no one size fits all. I think that's the number one premise, right? We really pay attention to the patient populations we're serving. I don't know. I got that question a lot, right? I used to get that question with essential tremor and people are like, how the hell are you guys moving so fast when YZ and X are so slow? Then with focal onset seizures and now with GE. I actually sincerely think, don't take this wrong, but I actually think this is a better question for the people who are going slow. I don't know how to slow down. I don't think any of us do. We're just doing what's in the best interest of those patients and the company. I think it's really the best interest of all of us, particularly shareholders, that those answers are like as quick as they can be. We do have a significant investment in recruitment. I think Tim talked about that before. We were not shy about putting our money where our mouth is to get these patients to be appropriate patients on the sites, being properly assessed. It pays off, right? At the end of the day, we spend a lot of time and money understanding where these patients are treated instead of listening to just noise about what they might be treated. I think data is everything these days, right? We know a lot more about all of us as healthcare users in the United States than people think. With that, we can help people understand if they could be good candidates in a clinical study. We have been doing a lot of that. It has been paying off greatly. Maybe sort of turn into, you know, maybe while you mentioned that, I guess, does that information help you when you think about a potential commercial launch? Oh, yeah. That information comes from commercial knowledge, right? Like in a sense, the way I could have answered your question is maybe you should just abandon the way we've been thinking about recruiting for these studies and just asking what happens when these drugs become available and how the patients become aware, how physicians become aware and use some of those strategies or clinical studies. That is what we've been doing. We've just been looking to the market as a market versus as a restricted unit. You know, that is basically what it is. Of course, because we're thinking that way, it maximizes a potential commercial launch as well on all of those conditions, on all of those diseases that we're aiming to help patients. When we look at that, it's much harder to find a patient for a trial than it is to eventually find the patients for the commercial drug. But we can learn a lot about all of the patients as we're going through the clinical trial recruiting. And so we've got very focused efforts and a lot of refinement on bringing patients into the study. But we keep all that learning going and keep in touch with any patients who are interested in participating as well. And I guess, you know, if you get approved in SCN2A and SCN8A, which is a rare epilepsy, right? Like I don't think it qualifies. It's not ultra orphan, but you know, I think we're talking 5,000 roughly so patients, you know, in the United States. How does it affect your thinking in terms of pricing, just given the fact that you're not, you're going to be launching into still orphan, right, but a much larger population of DEEs in potentially, right, you know, as you're suggesting, you know, like 12 months down the road? Yeah. I think philosophically it's very simple, right? You price for the indication you have, not for the one you're going to have. We need to price for 2A and 8A. Eventually, if like we get everything successful in the approval for the larger indication, then we can look into that again. The analogs are pretty clear, right? There is very little elasticity between the two, right? To speak like in technical, like payment pricing terms. Even if there was a lot, we would still price the same way, right? When you look into analogs for Relutrigine, I think there's a number of very recent launches that show that actually what's possible. They always start with a four or a five in front of the hundreds of thousands, right? You look into everyone's models right now, which I find a little interesting. We talk about other conditions that have 10,000 patients, for example, in the United States, and it justifies four or five companies and each one of them multi-billion dollars. Now, you look into a condition that is 5,000 patients and there's no competition. All of a sudden, it does not justify multi-billion dollars, which is, I find it interesting, creative math when people want to justify. This is a multi-billion dollar opportunity no matter what. You need to price on the appropriately for a rare population. Every time we test those levels of price, there are no restrictions. I mean, I think, you know, you sort of mentioned multi-billions, but I think, you know, in the slides, you still have like greater than $500 million for the SCN2A population. We're shy. We're shy people. I'm a shy person. Jokes aside, that's where we start, right? That's where we start with that. It's like if you don't believe on anything, you have to believe that it's at least $500 million to $1 billion for the skeptics out there. When you start actually doing the work, as we invite everyone to do the work, like now with the risking, with the acceleration, with the enthusiasm for patients and physicians to be these drugs, it is not hard to get to those numbers we're talking about. Maybe now turning to Ulixa. Go Ulixa. You know, was obviously such a significant event for the company and transformative. You know, how does the sort of pre-NDA meeting de-risk the story? Will you wait for the meeting minutes to provide sort of perspectives on the outcome, or is that something that we might have to wait a little bit for and wait for the minutes? It's an important step. I'll say de-risking is probably not a valid term here, right? What are de-risking? Like we are, as part of the evolution of the dialogue with the agencies, a very important step to confirm that the package that we have is appropriate for that filing. And that's all it does. If you want to call that de-risking, I'll be okay with it. But it's not exactly that we are going there with an unconventional package. It's not that we're going there with like half a controlled study to be in physicians for a minute. Like those are like two well-controlled studies with one well-controlled study being supportive that is essential. I want to like three studies in a sense on very clinically meaningful, clearly statistically significant results. From an efficacy side of the equation, it should be a pretty straightforward conversation. On the safety side of the equation, it's a pretty straightforward conversation as well. On the unmet need part of the conversation, it's very clear, right? There is no hair in terms of like CMC and other things that sometimes exist on those meetings. It's actually pretty well resolved, like package in general, but it's an important step, right? I can foresee like a scenario where the agency is like, this looks good. Like you can file. We're going to communicate appropriately. I think there is a scenario that there is a more robust dialogue about what. I don't know. I'm just like from a scenario planning perspective. The minutes might be quite important or the pre-meeting comments by the agents might be very important. We're going to have to get there in a few weeks to actually cross that bridge. It's coming up soon. For us, it's just a very important step that we've been planning for a while. Have you thought about applying for Breakthrough Designation or just given where you are with the program, you know, is it not necessarily that important? This feels like your question about the National Priority Voucher as well. I'll say instead of answering yes or no, I'm going to pose more of a question, right, for you. If we have an opportunity to present the value of the drug differently to the same reviewers, to the same people through a different mechanism, would you? I would say like, why wouldn't you, right? Maybe it's less about whether or not breakthrough would be granted, should be granted than the timing. Every opportunity you can to actually reinforce the package, the differentiation, I believe one should take. Of course, we always respect the agency and the staff and making sure that we're not putting burden on them that is unnecessary. It sounds like a logical step, let's put it this way. You know, we've gotten sort of questions around the sort of robustness of the day 77 to 84 endpoint. You know, can you sort of offer some perspectives on that and sort of how things may have changed over time? Yeah. We know what happened with the study, right? What happened is actually pretty simple. Every time point on the primary and on all the secondaries were positive. When faced with that in pretty much any trial or Pica study, Pica study coming up, and if I tell you that every time point, every endpoint were positive, there would be no more questions. For the splitting hair people out there, that's going to be my answer today. I guess another question I had coming from the data was, you know, sort of the duration of the treatment effect. You know, we did not see sort of the full sort of like a change of the Kaplan-Meier over the full, you know, course of the study. You did give us the plots, right? You know, with the error bars, but that was always sort of the difference versus placebo. You know, the delta could change, right? Not just because of the treatment effect, but because of, you know, how placebo performed. I presume, you know, from, you know, Essential Tremor patients, they generally do not get better, but there is definitely variability how they are doing at different time points. You know, maybe it would be helpful to just provide some context on how patients did on Ulixa over the course of the study. You know, when will we potentially see OLE data from ESSENTIAL3? And then the final one, if we go back to, you know, maybe it's helpful to remind people what we saw from the OLE from ESSENTIAL1, right? Yeah, absolutely. The first, I think it was a, can't remember if you called it, I think a phase 1b study maybe, so. 2b, yes, yeah. Or the other one, yes, yeah. It is very robust throughout, right? As I was saying, and I think if you were, if I showed you like the end of the study and nothing else, like drug and placebo, it would be like, these are very strong, very robust results. That is why I am saying this is a splitting hair scenario because I think there is nothing but splitting hair at this point in time, right? You pick those points and you are looking like, these are very robust, clinically significant, statistically, like let's move on type of scenario. To answer your question, it is actually interesting because you were saying when you talk to patients with Essential Tremor, you said two very important items there. One is it does not get better. If anything, what we hear, right, and what you're seeing now is that we asked the question how it in the last three years, it got better or worse. And 95% of the patients like go worse. Yes, it not only doesn't get better, but it gets worse. That's one. The second is it is variable. Remember, the actual idea of this endpoint comes from the premise that it is variable and therefore you have to assess the impacts on the previous week on the activities of daily living, not in the moments. When you put those things together, it's actually pretty simple to understand what happens. It's like over time, placebo is not that big, right? Placebo is actually pretty controlled, but it does vary because like it's actually the condition and not necessarily placebo effects. The same thing with drug to a different magnitude because you have a large drug effect here. What is really happening is like ebbs and flows of like those two parameters and then increased variability as it goes on is by no means a reduction of drug effects as one could imagine to be number one. Two is like what you've seen before is a very robust over time results. You might recall that our proof of concept for the randomized withdrawal study was done in the extension of the previous study of ESSENTIAL1. We actually got stable responders there, like several of them, over 20. We randomized them to be removed drug or to stay on drug. Those patients, several of them are still on drug today, like on years on drug. That should tell you about durability of effect. The vast majority of the patients on ESSENTIAL3 switch to the, it was an automatic switch, so meaning they could drop if they didn't want to, to the long-term safety study as we call. That's what we've been following then is for safety. Why would anyone take this drug once a day if they were not seeing an effect for years, for example? Should they do something from there as well? The other point we gave recently, we've been asked, right, are you there on the exposure that is needed for an NDA? We're like, yes. We know the minimum exposure is 100 patients, 12 months. When you put everything together, like it should be pretty easy to deduce that this is not only an acute, very strong two weeks onset effect, but it lasts very long and patients stay on this drug for very long and they have two benefits. It's a chronic condition. This would be a massive opportunity if it was not chronic. If this drug only worked for six weeks, this would be a multi-billion dollar opportunity. Like there are 7 million people with this condition in the U.S. It does work for a very long time. Actually, we do not know for how long because we believe for forever. One must admit that that opportunity is incredibly big. Marcio, I guess just to ask a follow-up in terms of the patients from ESSENTIAL1 that have stayed in open label extension, I guess can you provide some perspective on, you know, the number of patients and the duration? I mean, that would suggest, I guess, like patients who have been on almost for three years and, you know. That's right. What types of number? I mean, are we talking 10 patients, 20 patients? Yeah, yeah. For at least one year, I kind of gave you the number that we have over like 100, right? For six months, at least 300 because those are the statutory. We have over 1,000 individual like patients or volunteers, those with this drug. It is a fairly robust safety database. It is a pretty large number that has stayed for all the study. Interestingly enough, on the long run, the hardest part before was because they were associated to a site and they had to travel to the site and so on. When we switch everyone to the long-term safety study in Essential 3, right? What we call study 3, that is actually much easier for patients because they can be at home. Even the ones who were originally on ESSENTIAL1 switch to that study now. Some people ask like, why did you increase the size of that long-term safety? Why did you increase the duration? Guess what? Because there are patients from other paths of life, patients who were in another study, studies from Jazz and studies from Sage, that actually wanted to be, and we gave them direct access to Ulixacaltamide hydrochlorides. Marcio, have you, you know, since you did do, right, it was Essential 3, but there were two arms, right? Study 1 and study 2. Have you conducted an aggregate analysis between the two? Because that's frequently something that the FDA does. What color can you provide on what that outcome was? Yeah, yeah. Hypothesis 3 and hypothesis 4 that we put out are the one could call the combination of those studies. It's maybe slightly different than what you are suggesting, right? I think you are coming more from what you normally do for an integrated summary of efficacy type of or meta-analysis. It's incredibly robust, as you can imagine. Not only robust, I think what is super interesting there, you're going to have not to hold your breath to wait for this because we're going to show this at AN next year, is the pattern of response is incredibly similar. Patients don't know which study they're in, so they can't like just pretend, right? I would say it's like it's a beautiful piece of replication of effects, which carries a long way, as you know, with the agency as well. Because it's so clear, right, of course, have an influence when you combine the analysis on the standard error, on P-values, on things like that as well, if you want to talk about things like that. So it's a very robust, very clear effect that we see over time and particularly when you combine these studies. When we think about the market opportunity, right? You know, so we're obviously now talking about, you know, in this case, a much, much bigger price, right, or a bigger population. I think you have suggested sort of a pricing corridor of $40,000-$50,000. I'm just curious, maybe what pricing analogs you've used and sort of the research you've given that gives you comfort, you know, sort of comfort that that will sort of be maintained. Yeah. So it's actually very, very easy to land there, right? When you go through pricing analogs and there are a couple of questions one must ask. Of course, how recent are the analogs, how similar it is, the condition, effect size, and the population, right? The mix here is like part D, a big part, and then a smaller part, managed plans and so on, private. We have to ask the question as well, and what kind of price is possible, what kind of restrictions would be put in place, what kind of restrictions are we okay with versus not. When you take all that mix into account, it's pretty clear that you would be not serving reinvestment in research, which is what we would ideally do with all the dollars here if we charge $20,000 or $30,000, because there are no restrictions there, no zero restrictions in terms of access, and you would minimize the revenue and therefore minimize reinvestments of the dollars in R&D. Unlikely as well, if you go through like $150,000, that would not be reasonable, right? When you test the different levels here, I think the numbers you quoted, like when you consider $50,000, even higher than that, are appropriate. If you think about the situation, for example, with TZ right now, with two drugs, both of them about $110,000 wholesaler acquisition costs in the U.S., virtually no restrictions, both drugs like growing, right? Work quite well. Quite nicely. Last time I checked, the restrictions on those drugs growing are actually not the payer. It's because they don't have enough people in the fields. They keep adding people in the fields, trying to catch up with the actual demand. Bring back the math here and say, if at those levels there are no restrictions when the multi-billion dollar drugs are ready, combined, the market's about $4 billion right now. I think it's actually, Marcio, it's about five. Yeah, so I stand corrected, yes. So about five. Why some people are making a big deal about this market where huge unmet need and no nothing, like really nothing to help these patients. You know, at one point, you were thinking about developing Ulixa in Parkinson's disease. You know, obviously, those plans were shelved when you were not as cash rich of a company, right? And sort of got deprioritized. Is that something that would potentially come back into play for Ulixa? Or you have talked about sort of Ulixa V2, would that potentially be appropriate for that drug? Yeah. So there are a number of things here that we consider, right? Because we did not stop the thinking or the analysis during the entry into.