Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Corporate Update Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automatic message advising your hand is raised. Please note that today's call is being recorded. I will now hand the conference over to your speaker host, Daniel Ferry. Please go ahead. Good morning, and welcome to Praxis Precision Medicines' EMBOLD Study Results conference call. This call is being webcast live and can be accessed on the investor section of Praxis website at www.praxismedicines.com. This call is also being recorded. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Praxis views as of today, this should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking an obligation to do so. Please refer to Praxis' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Marcio Souza, President and Chief Executive Officer of Praxis. Joining Marcio on the call are Dr. Steven Petrou, Co-founder and Chief Scientific Officer, and Tim Kelly, Chief Financial Officer. After providing the top-line results of our EMBOLD study, there will be a brief Q&A session in which Marcio, Steven, and Tim will be available to answer your questions. With that, it's my pleasure to turn the call over to Marcio. Thanks, Dan, and good morning, everyone. I'm very excited to share with you some results from our EMBOLD study in DEEs. They mark a significant advancement in our ongoing commitments to improve treatment outcomes for patients. Firstly, we observed a 46% placebo-adjusted seizure reduction across this study. This is truly remarkable in such a severely affected population. In terms of safety, a critical aspect of any treatments, but particularly important in all DEEs, where patients tend to be heavily medicated, relutrigine was well tolerated and no discontinuation due to AE was observed. This underscore the potential for patients who have struggled with other medications and treatments. Most notably, we achieved an unprecedented level of seizure freedom, with five patients remaining seizure-free for longer than 28 days. No patient was seizure-free for such longer period of time before entering this study or experienced such effect while on placebo. I can't say how excited we are for those patients and for the broader community, and the implications it brings to the epilepsy and DEE community in general. Additionally, relutrigine-treated patients demonstrated a 75% median seizure reduction during the long-term portion of the study, indicating not only immediate but also enduring benefits for patients. Moreover, clinicians and caregivers have reported a disease-modifying impact, observing substantial improvement in patients' daily functioning. And lastly, these promising results have propelled us to initiate and expand the registration cohorts, aiming to further validate the drug's benefit and support its journey towards regulatory approval. Those results position Praxis further into disrupting the epilepsy markets. SCN2A and SCN8A alone, with over 5,000 patients in the U.S. and no approved treatment, are expected to have a peak revenue potential of more than $500 million. On top of that, the validation of the safety and efficacy brought by EMBOLD allows us to confidently expand towards the broader DEE markets, particularly the well-established population of patients already using suboptimally from both safety and efficacy, sodium channel blockers. That opportunity alone is expected to be well over $2 billion. Those are truly exciting moments, but before I continue to discuss the results of EMBOLD, let me hand the call over to Steven Petrou, our co-founder and CSO, who will discuss key aspects of the Relutrigine. Steve? Thanks very much, Marcio, and I appreciate everyone joining us this morning. Before we delve into the specifics of the trial, I'd like to provide some background on the two disorders we studied and discuss the broader context of developmental and epileptic encephalopathies, or DEEs. Additionally, I'll explain why we believe that sodium channel modulation by relutrigine has the potential to significantly improve outcomes, not only for the specific disorders we studied in EMBOLD, but for DEEs more broadly. As you may know, DEEs encompass a wide range of severe epilepsies, many of which are driven by mutations in one of around nine hundred known genes. These conditions vary in severity, but they all profoundly impact patients' lives, often leading to significant developmental delays and frequent debilitating seizures. The burden on caregivers is equally substantial, as these diseases often require regular hospital visits and intensive, ongoing care. Additionally, the high seizure burden associated with DEEs significantly increases the risk of mortality, in particular, due to sudden unexpected death in epilepsy or SUDEP. Within the spectrum of DEEs, SCN2A and SCN8A related DEEs stand out due to their severity and resistance to treatment. These two genetic DEEs are among the most severe, often manifesting from birth or early infancy and resulting in very high mortality rates, with most affected children not surviving into adulthood. Although these conditions are rare, about two thousand three hundred SCN2A patients and two thousand four hundred SCN8A patients in the U.S., the unmet medical need is immense. Currently, there are no approved medications, leaving SCN2A and SCN8A patients with even fewer treatment options despite their heavier disease burden. These children are typically treated with a combination of anti-seizure medications, which offer limited efficacy and often come with significant tolerability issues and complex treatment regimens. It's important to note, the EMBOLD study population was heavily pretreated, so any observed efficacy of relutrigine is in addition to standard of care, but maybe now, let me better introduce relutrigine, also known as PRAX-562. Relutrigine is a sodium channel modulator that was developed at Praxis and represents a novel approach to treating DEEs. Unlike traditional sodium channel blockers, the target channels in their resting states, relutrigine works preferentially on sodium channels in their hyperactivated states. This selective or functional targeting allows relutrigine to reduce pathological sodium channel function, such as persistent current, without impacting the tonic or resting state current that can lead to tolerability concerns. As a result, relutrigine has the potential to be more potent across multiple sodium channels while avoiding the safety issues that have historically limited the effectiveness of standard sodium channel blockers. Our preclinical studies were highly encouraging. Not only did we observe remarkable efficacy in the MES model, with excellent tolerability leading to a broad therapeutic index, relutrigine achieved complete seizure elimination in 2A and 8A DEE genetic animal models. Additionally, before the EMBOLD study, relutrigine was tested in over a hundred and thirty human participants across single and multiple ascending dose studies. Together with human exposure data from the EMBOLD trial, that Marcio will discuss shortly, our findings suggest that participants and patients are achieving exposures expected to be well within therapeutic ranges, as predicted from the animal models. Together, these studies demonstrated a favorable safety profile and significant pharmacodynamic activity in the brain, further supporting our decision to advance relutrigine into safety and efficacy trials. This promising profile across multiple datasets suggests that relutrigine's mechanism of action could benefit patients across a broader range of DEEs, reinforcing our commitment to improve outcomes in this challenging group of disorders. With this scientific background in mind, I will now turn the presentation back over to Marcio, who will walk you through the study design, the key results, and their implications for the future of DEE treatment. Thank you. Thanks, Steve. Let me now discuss in a bit more detail the EMBOLD results. Patients were randomized one-to-one to receive relutrigine or placebo. When assigned to relutrigine, patients stayed for sixteen weeks on drug. If assigned for placebo, during this period of sixteen weeks, they received placebo for four weeks and relutrigine for the twelve weeks remaining. After sixteen weeks, patients were eligible to continue receiving relutrigine for up to one year in the open label portion of the study, which is still ongoing. This being the first study with the drug, it was important and paramount that we observe the safety in patients. From efficacy standpoint, we set out to examine the change in frequency of motor seizures between drug and placebo, as well as the rates of seizure freedom. We have also examined the overall impression of change in multiple relevant clinical parameters by both the caregivers and clinicians. EMBOLD was blinded not only for the assignments of relutrigine or placebo, but also for the periods during the 16 weeks when patients received placebo or not. This design allow us for minimization of time on placebo, which is important due to the high seizure burden, while maintaining the integrity of the observation. The success of the implementation in this part of EMBOLD encouraged us to continue to use the design for the next phase of development, and therefore we will maintain the assignment periods blinded at this point. Now let's move on to the study disposition. 74 patients pre-screened, and of those, 20 were assessed at the study site for eligibility, and 16 matched the criteria and were randomized in the study. The study enrolled an exclusive pediatric population with confirmed mutations in the SCN2A and SCN8A genes. Patients had to be stable in their dose and regimen of background ASMs for more than a month prior to screening, and had a minimum of eight motor seizures every four weeks. The enrolled population mimics the severity of the condition in the real world... with patients presenting with seizures daily and early in life and having a high and unstoppable seizure burden. Enrolled patients have a median of over fifty seizures every four weeks, which unfortunately is a reality in this population. From a safety standpoint, Relutrigine was generally well tolerated, and the adverse events observed were expected for both the population and the intervention. The most common treatment-emergent adverse events while receiving Relutrigine were infection, vomiting, paresthesia, somnolence, and constipation. AEs were mostly mild to moderate, and no drug-related SAE was reported. During the course of the study, patients could reduce the dose of Relutrigine in case of tolerability issues to 0.25 milligrams per kilogram per day. No patient was required to dose adjust during the study. Now, moving on to efficacy. Patients receiving Relutrigine have seen a placebo-adjusted reduction in motor seizures frequency of 46% during the course of the study. These are remarkable results, considering both the severity of the patient population, who presented with over 1,700 motor seizures as a group at baseline, but also the duration of the treatment. Even more impressive and unexpected was the ability to achieve long periods of seizure freedom by several patients. This is very humbling, and it's worth reflecting on the fact that seizure freedom has never been reported in the population before, and it's clearly a meaningful outcome expected by patients and caregivers, which is directly associated with better outcomes in any epileptic condition. When we isolate the single periods of time where patients were either on placebo or drug, the results are also very dramatic, with 27% median seizure reduction in that month alone, paired with a minimum placebo effect, which is expected in this population. 13 patients elected to participate in the long-term open label part of the study. As of last week, eight patients on that group had data for at least 28-day periods available to be analyzed. When computing the change from baseline on that population, it's clear the effect we are seeing, with a remarkable 75% median reduction in motor seizures. It's worth noting that we see, as expected, an association between general better results, including seizure freedom and exposures, which are expected to be achieved by one milligram per kilogram per day. Moving forward, we're initiating all patients in the registrational cohort of EMBOLD at one milligram per kilogram per day. While the remarkable reductions in seizures should be more than enough to keep us excited about Relutrigine, it's truly meaningful to see gains in several areas observed by both caregivers and physicians, including the positive change in alertness and communication, together with notable improvement in seizure severity and intensity. I would like to take a moment to thank all the patients, their caregivers, and healthcare professionals involved in EMBOLD to date. We look forward to continue to working with them and expanding our partnership in this community. With such compelling results, it became our obligation to quickly move the program towards registration. With that in mind, and in anticipation of a positive result, as we've now seen in EMBOLD, we have planned our registrational cohorts comprised of 80 SCN2A and SCN8A patients. This phase of the study will have sites in Europe and the United States, and we are now officially open for enrollment. We expect this portion of the study to be sufficient to confirm the benefits of Relutrigine. We also plan to meet with regulators by the beginning of next year and align on a registrational program for the additional 100,000 patients with the, whom we clearly believe would benefit from Relutrigine. I'll now gonna open the call for Q&A. Operator? Thank you. Ladies and gentlemen, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Now, first question coming from the line of Yasmeen Rahimi from Piper Sandler. Your line is open. Good morning, team, and congrats on the data. I think the first question that clients are gonna be wondering is, how does this data compare to maybe other current approaches that are in development? Obviously, it's difficult to make apple-to-apple comparisons, but if you could just put it into context of what this data means from a competitive perspective, that would be great. That's question one. And then question two is, if you could maybe allude a little bit in regards to your plans into a broader population, like, what, what maybe the steps are necessary to do you have to engage with the agency? What would that look like? And how soon could you come back and communicate that with us? That would be really, really helpful. If we could start on those two, that would be great. Sounds good. And thanks, Yas. So on the first one, on how it compares, as you rightly said there, I think a direct comparison is very difficult. But, if you look at face value, as I think we should, when direct comparisons are not possible, there is not nothing in developments or that has been developed ever that comes even close to the results we're showing today. I think it's very important when you analyze data for the studies on such severe population, that you answer a number of questions. That one is whether or not the proper population was selected on the study. We know that DEEs are majority pediatric, with the high seizure burden, that they were identified properly before, so we check all those boxes for EMBOLD. Quite importantly, right, while we never expect or should never expect a very high placebo effect on this population when you select them properly, then we adjust properly for a placebo. And then when we look into that, the results we're seeing today are unbeatable, really, when you look across the board. So I think that's the not so humble way that I would answer that first question. But then when you take a step further and you look into seizure freedom, then we are unaware of anyone who showed anything even close to seizure freedom, and that should not be underestimated. I'll ask all the parents around this call to put themselves in the other parents' shoes that are taking care of these kids and the kids themselves. But having a long period of time without seizures is incredibly significant. We run this business for multiple reasons, but the primary is to give relief to people who cannot be in the room having this discussion with us, and I think that's what we are seeing today. On the second part about, like, how fast and what is the approach for the 100,000 patients or so with DEE that we believe we can address. So two steps, right? So one, we're taking the 2A and 8A out of the way, right? They are starting. We can recruit patients today for the registration or for the pivotal study, and that is already going. I think everyone should like pay attention to that as well, on how far forward we are in terms of really executing on those programs. For the larger study, we do believe a regulatory interaction is granted in terms of how we define the population, how we would be treating the population, if titration would be the same as we believe it would, to one milligram per day, and the auto titration that we see with relutrigine, and obviously, the duration of that study, the size, and so on. We don't expect anything unusual, but we're planning an interaction for early in the year, so we can start that other study right away. As I mentioned on the prepared remarks, that alone is over $2 billion, and that's what we look forward to explore. And then Tim, I apologize for sneaking in one last question. Given that, you had eight patients on in that 28-day period, as well as the long-term, you had two additional, could you talk about the homogeneity and the response among the small cohort of patients? And I'll jump back in the queue. Yeah. So for the patients in the long term, you never need to apologize, Yas, for great questions. If you look into the long term, right, we have eight, obviously gonna have the remaining of the patients as time goes by, between now and the end of the year. It's very homogeneous. We see all patients like with very good response. There are a significant number of them are obviously seizure-free, so they are 100% reduction now. And we continue to hope that they're gonna stay that way, knowing how severe this disease is. It's a huge feat, like we mentioned on the back, over 200 days, the longest follow-up we have seizure-free. I think that there is absolutely no one you can call, any expert after this call, that will tell you that was ever possible on this population, so very homogeneous. We know the dose associated with it. We know the titration that is associated with the highest benefit, and we're gonna be driving that on the next phase of the program. Great. Congrats again. Thank you. Thank you. Our next question coming from the line of Joon Lee with Truist. The line is open. Hey, congrats on the strong data, and thanks for taking our questions. Dr. Petrou's explanation on the functional selectivity of relutrigine was really helpful, and trying to understand how it could be differentiated from other sodium channel inhibitors. So the question is: How prevalent is the off-label use of sodium channel inhibitors for DEEs? And number one, what would be the washout period for the trials that you have in mind? And, you know, does this mean that the trial could, in theory, look like a randomized withdrawal? And what I mean is that if you are-- if the patient is on stable sodium channel inhibitor, and then you wash them out, is that, like, in essence, a randomized trial, withdrawal trial? Thank you. Yeah. So the for the current study, we allow patients to stay on the background therapy, because obviously the risk of status and other complications is very high. So we don't see necessarily from the get-go the need to remove the drug or to wash. Now, for patients that could do that during the study or after the study, as the concentrations of relutrigine increase, that would be an option, and it was in the current study as well. I think ultimately the goal is to have relutrigine being monotherapy for these patients. A cleaner drug with, like, less general complications, and we know those other drugs are pretty dirty in general. Now, to your first part of your question, and then I'll hand over to Steve to see if he has any comments here as well. For the first part of your question, when you look around the universe of patients that are being treated with these, right? So there are anywhere between a hundred and two hundred thousand of those patients. There are a couple of patients are very different, like the classical loss-of-function SCN1A patients or the LGS patients, like a subpart of the LGS patients. But outside of the domain, well, in that domain, it's about 30%, so general modulation. Outside of that is the number one therapy that is treated, being given off-label. The key limitation is tolerability. Like, the physicians attempt to increase the dose, and they cannot because they hit the proverbial wall, and therefore they have to stop. So they never really treat these patients optimally. That is a perfectly prized market to a drug that is not only better for efficacy, but also better from a safety perspective in a market that is basically that there is no competition, right? There is no one that could show something like this. But maybe, Steve, you can talk a little bit about why this mechanism, when you compare to others, in the market or in development, has no limitations, right? Yeah, absolutely, Marcio. So it's a great question, Joon, and if you think about it, sodium channels are the gatekeepers of all excitability in the brain. So unlike pretty much any other target, you have to pass through a sodium channel in order to be excitable and in order to have a seizure. Now, the issue is, it's the manner in which you interact with those sodium channels with a drug that determines the relative efficacy versus the tolerability. And I think it's that challenge that has held back sodium channels from being more effective than they are, and it's a thing that we tackled head-on. So that mechanism is central. If there is no Emax limit, as there is with other mechanisms, there is a limit in the actual properties of the drug. I think that's, in some ways, you know, where Praxis has really differentiated itself from that perspective. And therefore, sodium channels, you know, have got a lot of capacity to be used very broadly across the whole range of DEEs. Fantastic. Thank you so much. If I could ask one quick question, follow-up. No worries. I was a little shocked that you actually don't wash them off of existing sodium channels. So you're actually thinking that you let you keep the patients on whatever off-label sodium channel they're on and add on relutrigine, a better sodium channel. Is that that's the idea, and so in the trial that you just reported, like, how many patients were on baseline sodium channel inhibitor, off-label? Yeah. So the majority of the patients had some concentrations. We measure concentrations for all those patients as well, so we know that they were on therapeutic concentrations that they could tolerate. They are clearly suboptimal, right? So looking to the baseline, as I'm sure you're seeing on the deck, we're talking about two to three motor seizures per day these patients were observing at baseline. Like, we're now to the point that, I would say, we spared more seizures than they had at baseline as a group, like over two thousand. So imagine, like, as we continue to optimize this drug and actually remove those drugs, as we started to do it on a number of patients already with very good results. It does pose actually a ungating event as we allow for that for recruitment in future studies, since it's very, very difficult for physicians and for parents to remove the drug that is keeping this patient somewhat stable. So that was a key decision point for us and clearly works right there. I think it proves the point that Steve was just saying, this is a function of selective drug. It's not one more sodium channel blocker. Wow! Thank you so much. I'll hop back on the queue. Thank you. Thank you. Thank you. Now, our next question coming from the line of Athena Chin with TD Cowen. Your line is open. Hey, guys. Thanks for taking my question. First, on tolerability, how much dizziness or sedation was seen? And next, on efficacy, what was the onset of effect of relutrigine, and how fast did patients achieve that seizure freedom? Yeah. So thanks, Athena, for that. So maybe I'll start with the last, right? So the seizure freedom was associated with concentrations that are around like, or higher than about three hundred nanograms per ML. And we can easily get to that on the high end of the half milligram per kilogram per day, but certainly on the low end of the one milligram, and that's why we're moving all the patients to one moving forward. Relutrigine is a very long half-life drug, so it does take a while, like in the beginning, to get certain concentrations. So in the first few days you're really not to therapeutic concentration. But starting the second week of treatment, we see a good relationship between the reduction in seizures and the concentrations increasing. So it's not something that takes a very long period of time. And for seizure freedom, it does. It starts after a few months on treatment. That's when we see a more consistent effect, because I think consistency is quite important here. And I think that is actually as expected, right? So when you look into the preclinical work that we've done, all the clinical work over hundreds of healthy volunteers that we explore the efficacy and safety, PK/PD relationship for this drug, that's pretty much what we are expecting that would take. So it's good when things lined up in science as well. Gotcha. And lastly, what was the severity of somnolence or sedation? Okay, I am sorry for that, didn't address. So it was actually the incidence was not that high, was mild. As you're seeing, paradoxically, we see increase in alertness as well on this cohort of patients. So I think what we are seeing here, it was actually to Joon's previous question, right? There is stacking it up with a number of other medications. You start triggering a little bit the limitation of the other medications as well. So removing them is what we see as the issue, but none of them led to discontinuation or to any, like, more problematic. So everything was mild to moderate. Got it. Thank you. Thank you. Thank you. And our next question coming from the line of Yatin Suneja with Guggenheim. Your line is open. Hey, guys, let me add my congratulations as well. Very nice results. Just a couple from me, mostly clarification ones. How should we think about the placebo response in this patient population? Our understanding is that it tends to be a little bit higher than 2% that you have observed in at least the single 28-day period. So that's one. And then help us understand this log transformation estimate that you're using to drive placebo-adjusted efficacy at 16 weeks. Sure. Okay, thanks for the question, Yatin. So, I think that this is the first time, right, that this population is studied properly. So I'm not sure that is a benchmark that we can go and actually look for from a placebo perspective. This is throughout the preparations for the study, when we were talking to key opinion leaders and to parents, we heard again and again, right? Those patients stay pretty constant. They have a little bit of variability throughout the month, but that shouldn't be an expectation of placebo. And I think what we're seeing it, it's similar to that. There is some variability coming in on the study and during, but it's by no means anything exaggerated in terms of placebo. So I think it's as expected. or if you go back to previous conversations, we had a webcast and, other calls, we would also talk about, like, those are intractable. This is not your, I don't want to minimize that, but run-of-the-mill, DE, where you see a lot of the patients spontaneously getting better, throughout, like, a short period of time. We don't see this as incredibly severe patients, so we were not expecting placebo effect, and that's what we're seeing. As far as the log transformation, I think that is another, maybe I'm going to use run-of-the-mill again, right? You're looking to, virtually every drug that's being approved in epilepsy, end up with a non-normal, baseline, right? The distribution, like, it's not fitting, like, the methods are. If you look into, it's a thousand seizures, and the other one is, like, fifteen seizures. So in order to do a proper correction, we try to bring them to the same space. And the way to do that, the most simple way, the most acceptable way, you look into both Sympazan studies, for example. That was the primary analysis, exactly the way we're doing. You bring them to the same space, and then we can compare them. So nothing unusual there either, just, like, trying to normalize the patient so we can compare them better. Got it. Very helpful, very helpful articulation. One more question, if I may. Sure. And this is a specific question that I just came from an investor. Could you just talk about your approach to DEE? Because our understanding is that, you know, sodium channel blockers are contraindicated for some populations like Dravet. So how would you be able to go after broader DEE? Would you just not go after certain indication where the sodium channels are contraindicated? Just curious to understand the dynamic, how it plays out from a regulatory and development standpoint. Thank you. Yeah, I know, absolutely. So that is again 150-170 thousand IG patients outside of Dravet, right? So maybe we start with that. I think there is a general obsession with this one indication because there is a lot of approved drugs. They work pretty well, and people love filing on approved drugs. But it's actually not contraindicated. Like, first generation, second generation should not be used because of pretty bad multi-channel effect that they have. So maybe just go back to the science there on anyone that looks. Actually, the bar for contraindication is very high, and people use that term very liberally. But it's not where we would start, mostly because there's a number of drugs that work pretty well for that patient population. We don't see the unmet needs on the remaining hundred thousand patients that isn't anything, whether or not is a 5- HT mechanism or something else that wouldn't work for those patients. And a sodium channel does work, it just has very, very severe limitations right now, and we're removing those limitations. So, for whatever markets that we think SCN1A loss of function, which should be Dravet, but it's a little bit expanded from that, is you can multiply that by ten, and that should be the market for GE that can be addressed with sodium channel modulators. So there's no need to talk about the small part of the market that is already fulfilled. Very good. Thank you so much. Thank you. Thank you. And our next question coming from the line of Douglas Tsao with H.C. Wainwright. Your line is open. Hi, good morning, and congrats on the results. Maybe, Marcio, I think it would be helpful or just be curious to get your thoughts on how you're thinking about, you know, 562, in the context of SCN8A versus PRAX-22, where we also got some very impressive results. I mean, how do you see the two therapies sort of sitting next to each other in the market? You know, who would you, you know, do you think one would be sort of the initial treatment versus 562? Thanks. Yeah, no, Doug, thanks for the question. So if you break down our approach for Relutrigine to DEEs in general. So one is the SCN2A and SCN8A, and I want to be bringing us back, SCN8A is a huge unmet need as well, and that's pretty straightforward, right? No one really doing anything, and we're in registration stage now. For two A, it's not that different in a sense that we believe the needs are complementary here. One could imagine, like in a few years, that you would have a maintenance treatment with PRAX-222, and like a control on top of that of sporadic seizures and so on with 562 or Relutrigine. So very complementary. There are other spaces, and I'm sure you can think about more than I can right now, where you have this duality of two mechanisms actually getting the maximum out of a disease, and that's how we are looking to this. And I agree with you, the results with 222 are equally impressive than they are here today. So it's good to be in a situation that we can help patients multiple ways. But as we move forward, really focusing on this larger GE markets as well, which is both many more patients, thousands and thousands of patients without an approved, adequate treatment. But also from a market opportunity perspective, I think brings the ability for us to continue to develop these drugs for other patients with GE. If I can, on a follow-up: So obviously, you know, I think everybody's initially gonna focus on the seizure reduction numbers, which are really impressive. But when we think about the potential of the drug, I think what seems very compelling is sort of the other benefits that we saw in terms of patient sort of verbalization and awareness, et cetera. Just maybe if you could provide some context how that compares to other treatments on the market and the standard of care, you know, in terms of the rates of improvement that you saw with relutrigine, you know, in EMBOLD. Thank you. Oh, thanks. Thanks for that as well. But like, it doesn't compare, right? Because if you look into the rest of the markets, unfortunately, may I say, they actually adds to already a very severe disease. They reduce alertness, they reduce communication, they oftentimes increase the severity of seizures when the therapeutic levels are lower. They have to be given multiple times a day for that not to happen. There is no. And right now, in developments or off label in the market, that seeing the consistent improvement in alertness, in communication, reduction in disruptive behavior that you're seeing with relutrigine. It was actually quite cool as well when we were analyzing the data, that you're seeing both the assessment by the caregiver and the physician to be almost identical, right? Those are independent assessments done at, like, completely different settings and mindsets, and when you look into that being consistent, like, you truly believe that these patients are doing significantly better. As we're reviewing the data with the principal investigators, over the weekend, I think what we heard from them was: This is exactly what we're seeing in our patients, and it's very unusual to actually see people who are excited about participating in the next phase of development, because they were not expecting to see patients doing so well, and they are doing that well. So yeah, we shouldn't minimize, and I appreciate the call out for us not to minimize that impact. Great. Thank you so much. Thank you. Thank you. Our next question coming from the line of François Brisebois with Oppenheimer. Your line is open. Hi, thank you for the question, and congrats on the data. I was just wondering, in terms of the you know, specificity here and the strategy behind the pre-screening patients, the 74, and then 21, and the eligibility of 16. Can you help us understand what goes into that, just making sure that you have the right patients and why, you know, from going to the prescreen number to ultimately the 16, why, you know, what is so restrictive, and how does that translate into the market, you know, down the road? And then I'll have a follow-up. Thank you. Yeah. So thanks, thanks, Fran çois. So I think they all going to call that a Praxis special, right? And maybe another underappreciated aspect of what we do. When people often ask us, like, how can you enroll this study, like, faster than company Y, Z, W, five times, six times what you're doing. And we do actually conduct a lot of the prescreening ourselves. And by prescreening, what I mean here, like, most companies will not even show you those numbers, right? Because they wouldn't have those numbers. They wouldn't be done in-house. And what do we mean by that is, like, geographic location, ability to be on the site or ability to participate in the study. Are they stable on a dose of the medication? A number of things, right, that you can imagine. They couldn't have status three months before getting to the study, which unfortunately is pretty common, so it wouldn't be able to hear. So I think that number, what you see is really the ability to not say the Praxis machine at work on actually getting to know these patients, and I can't thank enough my team to actually being able to do that so diligently every single day. It's not that different than what you do with essential tremor, with thousands and thousands of patients being prescreened, right? So that is the same. When you look into the actual, normally what people talk more about, that between the 21 and actually patients being randomized, I think it's your typical, patients who are unfortunately had to use another medication during the screening process, so they are no longer eligible, or they had to be hospitalized or something like that. So nothing unusual there. I think those are more the usual rates, that you see throughout. I think what you're going to see moving forward, and we're already hearing from. If you look into our press release, we had a joint statement from all the major patients organizations, and what they told us is this open up to a lot more patients that are really available in the US, but they were not willing to participate on the first study, right? So now people are willing to participate on a second and third study and things like that. So all in all, I think it bodes incredibly well and show, one, our level of transparency, but two, our level of diligence. That's very helpful. Thank you. And then in terms of the, you know, read-throughs, are these patients, in terms of DEEs, are these maybe the hardest patients, the worst, or are they all, you know, they all have their difficulties, you know, regardless of the population? Or is it like, look, we, we got an SCN2A and SCN8A, so the odds of this working in other DEEs is actually a lot stronger because this was a very high bar. And then maybe if you can touch on the read-through to PRAX-628 as well. Thank you. Yeah. So, I would say we've been pretty consistent about this, right? Those are the hardest patients. I think if you ask around, like, to key opinion leaders, look into these patients, one of the key limitations on the study, a lot of them couldn't leave their house because, like, the travel alone would be so disruptive for treatments. So you can imagine that. I would say on one side of the spectrum, you have those patients. On the other side of the spectrum, you have, like, the older patients that people still call them DEEs, but they are, like, on their teens or older, that they are a lot more stable, and they are arguably easier. So as we move from these incredibly severe patients to a larger population, one could argue that the bar actually lowers, meaning it's easier to treat them. Now, every seizure matters, every patient matters. I'm not trying whatsoever to minimize the severity of a single motor seizure, because those things are incredibly disruptive. They lead to SUDEP, they lead to death. So we should never try to compare patients. For that patient, that seizure is very important, but it bodes incredibly well from our probability of success. Now, to the second part of your question, right? How does it look into 628? Well, imagine what you can achieve on a disease that is less severe, that is less complex, that is focal onset seizure. Because these channels in the brain is not quote-unquote "on fire" 24/7. It's not hyper excitable like the entire day. It's not firing like crazy. It sporadically does. And the drug being available, which is the important thing, at therapeutic levels that are around the same that we have here, that bodes incredibly well. I'll end with this part of the conversation with like a comparison. With seizure freedom with relutrigine around like over 300 nanograms per mL. So that is about three times the MES's EC50 for 562 or relutrigine. We are starting to dose patients with 628 at about double to more of that. So you can imagine what can happen, right? Should we close our eyes and imagine a situation where, like, seizure freedom would be the norm on treatments moving forward after 628? I think we've got to give ourselves the liberty to dream today based on these results, but go back to earth and look into what we need to deliver. That is a very solid like best in class, best ever results for 628 as well, and that's what we're expecting next year. Thank you. Congrats again. Thanks. Thank you. And our next question coming from the line of Ami Fadia with Needham. Your line is open. Hi, good morning, and congrats on the strong data. A couple of questions just with regards to how we should think about some of the sort of design elements as you think about the registration study. How could sort of the efficacy results differ if you initiated all patients on one milligram per kg? And I'm looking at slide 17 and 18, where we sort of see on slide 18, response rates from patients who dosed up during the double blind period. So, you know, should we anticipate a improvement in response rates if all patients started at a higher dose? And how should we think about impact should patients not have other sodium channel blockers on board at baseline? If you could sort of help us think through that, and then I have another question. Yeah. So, I mean, I think everything we know right now, that is, a good dose response between half and one milligram, or maybe I should say there's a good exposure response, right? Because at the end of the day, that's what matters, if the exposure we're getting. And it's a positive trend as we increase the dose to one. So when you go back and you start those patients and give them more opportunities to be at those exposures, we can only imagine the results to be more consistent and potentially better. So that's how I would imagine that. Now, on patients not being on sodium channel blockers at baseline, I think for SCN2A and SCN8A, on the registrational cohorts that we are running right now, it's gonna be very rare for that to happen, just because those patients are often treated. So they would be able to remove that during the trial, as was possible during this study, like 25% increments on the reduction after a given point in time, but not starting. I can't see how that would be possible with the risk of status and the risk of death being so high on this patient population, right? Now, for the larger IG population, which I think we're gonna have, like, a significant number, what we would see, and, and we believe, like, based on one, at least one patient that we know could not tolerate any other sodium channel blocker, and that we were in our study, I think what you would see is what you expected, but this mechanism works. I think it's, it's known that it works. So the question is whether or not they can get to therapeutic levels or they can tolerate, which today is a great step towards that. So we expect them to do really well, on 562 slash relutrigine. So, we don't see a limitation there, potentially even being able to get faster to better resolution of seizures because there is no other things impeding them to get to that point. But, I think for today, we just celebrate the amazing results and continue to plan as we move forward. Great. Just one more question, if I may. As you think about a broader clinical development in other DEEs, you know, you talked a little bit about Dravet syndrome, but outside of Dravet syndrome, should we assume that you would think about a trial in all DEEs other than DS? Or would you sort of, you know, is the work that you're gonna do to identify which specific DEE subtypes would be more suitable? Yeah. So I mean, the way we look into this, just very extensive research, both on use of drugs, like seizure rates, like effectiveness, tolerability, you name it, right? So I think where we are landing right now, and that's a discussion we want to have as well with regulators, is phenotypically driven versus the genotypically driven treatments. And what I mean by that is, high seizure burden, not being able to control, they would be eligible to be on the study, and we would treat them. So it's kind of all, it's the all category that you just mentioned. Got it. Got it. Okay, thank you so much. Thank you. Thank you, and our next question coming from the line of Joel Beatty with Baird. Your line is open. Hi, congrats on the data. First question is, how much reducing or removing of other medications did you see over the course of the study or in the long-term extension? Yeah, we're just seeing on the long term, Joel. So during the study, actually, we haven't seen that happening. So I think there was a caution from the investigators and the parents as well on keeping things stable. As the things are going well, I think people tends to want to keep them reasonably stable. And now in the long-term extension, seeing people being a little bit more adventurous in terms of reducing the side effects by removing those toxic meds, background medications. Okay, thanks. And then, can you provide any more details on the one patient in the placebo group who is not eligible for the efficacy assessments and why that was? Yeah, so that patient was here in the US and could not comply with study procedures, so it could not be assessed. Basically, there was no data in the diary, no evidence that the drug was being taken, so that's why it could not be assessed. Got it. And then maybe one more follow-up. Can you provide any context on what type of enrollment speed to expect in the study that's just starting now compared to the study that is reading out? Yeah. So we were able to enroll this study. I would say from effectiveness perspective, give or take, in about three quarters. Obviously, with the pace, we only had two sites in the US, one site in Europe, so there was a hybrid approach as well. We could send a medical team to their house, as we're gonna continue doing. As we move forward, we're gonna keep those sites. They did a phenomenal job, and they're gonna continue to work with us, but we are expanding as well, quite significantly, right? For our scale, quite significantly. For other people's scale, it's still gonna be a small number of sites. So we think we can deliver on about. I would say no promise right now. We need to get off the ground, but probably about the same time, to give or take, like a quarter or two there. So our goal is really to get this drug submitted by 2026 to the FDA and get an MA, a market authorization, an NDA, EMA outside that year. So we're marching towards that. We pretty strongly believe that with all the support we're getting from the patient groups, from the physicians in general, that's possible. But early days, so we need to work hard on that. Great. Thank you. Yeah. Thank you. And our next question coming from the line of Kambiz Yazdi with Jefferies. Your line is open. Hey, guys. Congratulations, and maybe just following up on kind of the breadth of the program. Would you consider development in non-sodium channel DEEs? You know, you saw some kind of anticonvulsant activity in some PTZ-induced preclinical seizure models, so just wanted to get your perspective there. Yeah, yeah, absolutely. We look at this drug across PTZ, we look it across MES, we look at it across other genetic epilepsies. We see efficacy, and it was back to the reason that we discussed with Joon earlier, that all of these mechanisms converge upon the axon initial segment, where, you know, a part of the neuron where the sodium channels are in very, very high concentration to determine the excitability. Because they all have to pass through that node, they're all gonna be subject to a mechanism that can interact with the sodium channels at that target. So we do see a lot of potential outside of etiologies beyond sodium channels for this disorder, and we've got enough evidence, I think, preclinically, to show that that's trending in the right direction, for sure. Thank you, and ladies and gentlemen, that's all the time we have for the Q&A session. I will now turn the call back over to Marcio Souza for any closing remarks. So thank you very much. Thanks for being in the call today, but I would say my real big thanks goes to the patients that participate on this study. I definitely wouldn't be here without them. It's exciting times for us. It comes with great responsibility. Every time we have a drug that works this well, and it's twofold. One is to make sure we don't screw up, and then we actually get this done, and we are very diligent. And the second, what I would say, is for the team at Praxis, they put all the energy and all their hearts towards getting today's results. So definitely onwards and upwards in terms of where we are. We're gonna enroll this study quickly. We're gonna get this drug submitted, and our commitment is really to help these patients and to get, like, everyone in a much better state than they are today. So thanks for joining. I'm sure we're gonna have a lot of follow-up calls, and appreciate the support as well. Take care. Ladies and gentlemen, that ends our conference call today. Thank you for your participation. You may now disconnect.