Welcome, everyone, to the next session. It's my pleasure to be hosting the Praxis Management T eam. I have with me here Marcio Souza and Tim Kelly. Thank you both for taking the time to join us today. Maybe, Marcio, if I could request you to just kick us off with some opening remarks and how you're thinking about priorities for this year, and then we'll go into some questions. Yeah, absolutely. No, thanks for the time, once again. It's exciting to be here with you in a not-so-exciting market out there, or maybe very exciting, right? It depends on how one wants to face it. I don't think, like, despite that, anything at Praxis and what we are doing changed. Maybe that's why I started that way. We are very well capitalized, and that's a luxury, I know, these days. What that does is not only like money in the bank, but most importantly, it's the ability to deliver on all four clinical stage programs we have and to advance some of the preclinical studies that are our programs that we're incredibly excited about. When you look into the next 18 months, two years, maybe if we can expand the horizon a little bit, which is probably very advisable at this day and age, we have the programming focal onset seizures and generalized with vormatrigine or previously known as 628, reading out RADIANT pretty soon, mid-year. Second study, POWER 1 reading out by the end of the year, the start of POWER 2, and that's all together serving as what we're hopefully going to be able to see next year with all going the way we expect to, an NDA being filed for this program and incredibly exciting, the pace and the ability to potentially really revolutionize the epilepsy, and particularly for those patients with intractable adult conditions. If it was only that, I would actually argue that there is enough excitement, and we can spend the entire hour or more talking about it. We do have the DEE programs as well reading out. EMBOLD, which is recruiting really well for SCN2A and SCN8A patients. We've been recruiting since late last year. The expectation and the guidance we gave publicly is to have the readouts in the first half of next year. I think the way we framed in our previous conversations, Amy, was we're giving a no later than the beginning of next year because we see the pace of enrollment right now. We're very satisfied with that. If it continues as such, there is an opportunity here for flexing positively. Right now, we are committed to the first half of next year. Maybe one of the most exciting from not only a patient-serving perspective, but from an overall market potential perspective is the EMERALD study. We are starting the study right now. We're going to be talking very soon. I believe you're all going to be receiving an invitation in less than a month for an analyst event that we're going to be hosting to discuss our DEE programs. We're going to go in detail on how we see the market, what is the EMERALD study design, what is the EMBOLD progress we made, some new analysis on EMBOLD, and why we're so bullish about that, but even the depth and the breadth of the overall DEE programs we have with the ASOs and so on. Stay tuned to that. It's coming up pretty soon. Maybe closing on the DEE parts, the progress that we're making with 222, where elsunersen quite nicely, finalizing the study we have in Brazil in the near future, and starting right now as we have the wheels moving on the phase III in the U.S. as well. Of course, I would be remiss not to mention that we're still wrapping up the studies in essential tremor for ulixacaltamides, and that readout for both Study 1 and Study 2 are going to happen in Q3. Quite eventful sets and a lot of stuff for us to talk about and to be excited about. Okay. Yes, indeed. Maybe just following up on your comments related to maybe just what's going on and maybe specifically with regards to tariffs. I know right now, Praxis is not commercializing a product, but as you think about all of these drugs that are moving forward in the clinical development pipeline, does this change anything with regards to how you start to think about your manufacturing-related decisions down the line? Yeah. I strongly believe that our role of management team is to execute in the present, but live in the future, right? We have been discussing a lot and staying on top of what's going to happen in two, three, five years to the extent that one can predict. We have been focusing on the things that are not going to change. Some of those things that are not going to change are the needs for these drugs, right? When you think fundamentally that, and I'm very, very lucky to have a phenomenal CMC team who has been for a few years now saying, let's spread the risk in terms of structurally where we are. We have a fair bit of the manufacturing done in the U.S. already. That is helpful in situations like this. We still do and rely quite heavily, I'm not going to say not, and just sugarcoat it on materials coming out of Asia, particularly China. It is disconcerting when we don't consider that as a general country, but I also think that everything is temporary. We're adapting. Thankfully, it's always starting materials. It's not something like towards the ends and the value-added parts that we're still doing in the U.S. and Europe. I think at this point in time, it's a small impact, if any, but it's something we are not only monitoring, but building redundancy around it. Okay, great. Maybe just with regards to all the changes that we've seen with the HHS and the FDA, and I'm sure you've had recent interactions with the FDA, at least in relation to the EMERALD study. Any changes that you've seen as an industry? Is there something that's going to shift as kind of you guys think about your own kind of strategy around regulatory interactions and such? Yeah. I do not think the sky is falling. I really do not. I think it is a very easy position to take and to panic. In a sense, it is quite the opposite, right? The review divisions for the most part have been, to our knowledge, intact. Of course, I can express my opinion about whether or not the means and the methods that were used are ones that I believe should be the most effective, but it is not my business to do that. It is just to understand what happened, what can we do, how can we work productively with the agency. I can tell you I have a very recent interaction with the FDA in the last few weeks, and it was very smooth, very straightforward, very professional, as it tends to be historically. We are reassured by seeing that some of the key players we interacted historically being there. Of course, we were sad to see some of the leadership go. At the same time, the show must go on. Our role here is really to build even stronger relationships and to facilitate as much as possible with the highest quality applications so reviews can be done on time. I'm cautiously optimistic that we are going to figure this out as we always did in the past. Okay. All right. All right. Let's dive into some of your very interesting set of assets in epilepsy. Let's start with vormatrigine. Now, maybe if you can just quickly remind us how that's different from some of the other sodium channel blockers that have been developed or are out there, and maybe then we can talk about your phase II, phase III. Yeah. There are the nice thing, and maybe I'll segue from what you just said, right? This mechanism is known to be fundamental to control brain hyper-excitation and a few other functions for decades and decades. We're coming from a foundation that we know how important this target is. That is good news, right? Because now we can ask, okay, if it is so important, what are the good things about it? What are the things that we could improve upon? Of course, we don't always know what the things we can improve upon and how to improve upon. On this case specifically, what has been very clear, right? We've looked through the literature when we talk to the experts in the fields that efficacy has not been the issue with anti-seizure medications. I think there is a little bit of a misconcept sometimes that there is this level of efficacy. The problem is patients cannot stay on those drugs because they cannot tolerate or because there are DDIs that interfere with other drugs therein and so on and so forth. You go one step deeper and ask why most of the tolerability issues are occurring. It is particularly because we've been using hammers instead of precise tiny screwdrivers to fix those channels. What vormatrigine and obviously relutrigine as well attempts to do here, and we believe it's doing quite well, is to modulate the function of the channel when it's firing in a way that is not physiological. When it's firing like a lot as in a seizure condition. If you look into our very early in vitro electrophysiology studies, to our in vivo studies, to our early human volunteer studies or health volunteer studies, and then to the PPR and so on, every single step of the way, this hypothesis has been playing positively to vormatrigine. What do we expect therefore from that, right? We are going to have very high safety and efficacy thresholds, right? That is going to result in a quite positive benefit risk. That is what we are expecting from this drug. The studies that are going on right now, you are going to need to see when they actually read out what we are seeing there, but that is the expectation. There is nothing precluding us from seeing that, which has never been seen before. What is on top of that? What is the cherry on top, right? This drug is incredibly potent, incredibly selective, and we've seen that through the preclinical and clinical work we've done. It's also incredibly convenient. It's once a day, an oral solid you can take in the morning or in the afternoon. We're presenting at AAN this week about the lack of food effects, which sounds like a small deal, but it's a big deal for patients. Everything in the profile from a basic pharmacology to an applied pharmacology has been optimized to an ideal drug for these patients. That's why we're so bullish about it. You have a phase II, phase III registration study that's ongoing, that's POWER 1, for which we're going to expect top-line data later this year in the second half. Can you remind us of the study design and powering relative to what we saw in the phase II-A? I'm sorry, give me a second. I'm sorry, there was a disturbance here. What's the study design in terms of powering and dosing of the study? More importantly, what would be success for the study, just given the strong data that you saw in the phase II-A? Yeah, absolutely. If we look into POWER 1, right, the study design is a 12-week study. The first six weeks, all patients take 20 mg of vormatrigine or matching placebo. The following six weeks, they take 30 mg or matching placebo. It is one-to-one randomized. We are expecting or we're requiring for patients to have at minimum four countable motor seizures before enrolling on the previous four weeks of the study. Normally, when a study sets the parameter, which is pretty common, we end up with around 10 motor seizures like in the median right before, right? It is a fairly large number, right, when you think about those patients. What you're expecting to see here is a combination of two things, really. One, and maybe the least important, although it's going to be measured on that, is a very significant reduction in seizures. I say at least important, and most people are going to think I'm completely insane by saying that, but knowing that mechanism is effective, knowing that there are drugs that deliver on that, the competitiveness really comes from the combination between the reduction in seizures, the achievement of large periods of time without seizures, and the ability to stay on the drug. One of the biggest unmet needs, if not the biggest unmet need when we ask physicians, when you ask patients, when you look into claims data, when you look into prescription data, is maintaining patients on drug, right? That comes from drugs that are safe and well tolerated. Yes, adding 30%, 40%, 50%, 60%, 70%, you name it, percent reduction in seizures on top of that is incredible. The real necessity is the combination between the two things here. We believe that vormatrigine is uniquely positioned to deliver on both of those. It's very interesting. How would you generate the data to really demonstrate that patients are able to stay longer beyond just sort of what you need to have from a registration standpoint? Yeah, yeah. Of course, we're going to have phases here, right? We're going to see what happens with patients in RADIANT. We're going to talk about that from both safety periods of time without seizures, seizure freedom as some call, the safety tolerability. We're going to start building the open label extensions after that. How long, how well, what is the retention? We know retention in epilepsy studies has been not great, right? We have 20%, 30%, 40%, 50% of patients discontinue right after the controlled phase of these studies. Small gains there, and I'm not guiding for small gains, but I'm going to say even small gains on retention are quite meaningful on a market like this where about 3 million patients exist in the U.S. alone. To POWER 1 is a longer study for more weeks. We start to see a little bit more of that data on the safety, tolerability, retention in general. As POWER 2 completes, which we have not talked yet about, but is the second study for registration here, we are going to have sufficient and a lot of open-label extension data. That is where we are going to start to see these rates of maintaining the drug, what is the ability to reduce background therapies, which is super important as well from a safety perspective, ultimate seizure-free rates, and so on. It is a package that instead of waiting several years to be built, we are going to have before the end of next year. In the next few conversations, I am assuming we are going to have a forum like this next year. We are going to be talking about POWER 1 results. We're going to be talking about what POWER 2 is happening and the expectations for that, but primarily for the overall package for this drug. That's unique as well that in such a short period of time, all things considered, we're going to be able to fully characterize what this drug can do for patients. Okay. You also have the phase two ongoing, which is actually an open label study. That reads out earlier in the year, which is around middle of the year, the RADIANT study. That is evaluating patients with both focal and generalized. Maybe just with POWER 1 ongoing, right? What is the purpose of RADIANT? How does that inform maybe even POWER 2, which you sort of alluded to a little bit here? Yeah, yeah. RADIANT is our intent. I think philosophically what we've been trying to do with the vormatrigine program is to learn very quickly, but very efficiently on what's the best way to address the next step is, right? We did the PPR, as you recall, last year. That gave us great confidence that drug's in the brain, that it's doing something for the seizures. RADIANT and what RADIANT is really attempts to do are a number of things. One is what happened to the pattern of seizures when we start 30 mg once a day. Patients take that for eight weeks, right? Is that a very dramatic, very fast resolution? Is there a slower, still dramatic, but maybe towards the end? Is there a pattern here? Is there an exposure response here? Things that you would take like a significant number of arms and ears to answer that you can answer in a very compacted way while continue to execute POWER 1. What we know from translational works, what we know from previous work that's been done in epilepsy is that there is a very, very high translatability between animal studies, when done properly, to starting those in controlled studies or open-label studies in focus at seizures or generalized seizures. Now, if you were close to the minimum there, I think we would say, well, there's a little risk here in terms of the dose. Maybe the dose should be higher or so on. But we are really much higher than the minimum, right? So we knew that either on RADIANT or on POWER 1, we were starting already from a place we should expect robust efficacy. The question becomes, did we push to the right place in terms of the dose? Is there efficacy left on the table? That is how it informs POWER2, right? If we believe after reviewing significance data in RADIANT that maybe 40 mg would add extra efficacy, extra seizure freedom, whatever it is, we have an opportunity to start POWER2 with that. It gives us an opportunity to actually get a significant number of investigators experienced with this drug to continue to advise us and to help on the development to accelerate the overall development and our overall goal in the future to be the first line, right? You do not become first line by just running a few studies. You become there by creating an entire ecosystem that understands how much better the drug can be for their patients. While the use initially is going to be third line, we want to move very quickly towards that. We believe strongly that the only drug in development right now that could make that move, if things considering being positive, would be vormatrigine. Now, also the data that you generated in the phase II-A, that was for the 15 mg and 45 mg doses. To what extent does RADIANT give us some insight into what POWER 1 can show from a response rate perspective? Maybe if you could sort of throw some light into that and maybe just for our listeners, remind us what doses you're testing. Yeah. Yeah. Yeah. I think what we're going to be able to see here, right? There is the base case that we see like a very clear efficacy and safety, as I mentioned before, and we feel incredibly confident and we'll continue to move forward with the program. What would be super interesting is we intend to build like a very quick PKPD modeling with this data is if we start to understand that is there or not at the levels we are, since we are so much higher than anyone else ever dosed these patients from a multiple perspective of the MES EC50, where there's still margin there to push higher in terms of the potential for efficacy and whether or not that is associated with certain concentrations. That would be a key insight from this data set, right? If we see more seizure resolution, higher seizure-like reduction towards the upper ends of the exposure, what it's telling us is go ahead and push the dose higher because then we're going to get more people there. That's how it would inform us here. It's been rare in epilepsy that when you are on the higher ends, there is more efficacy to be extracted. Some investors ask me, why not just go straight? You can go to 45. Arguably could go even more if we did a little bit more of phase I work. Why not go higher? There's not a lot of empirical evidence that just keep going higher and higher is going to do any better, right? Especially on the levels we are right now, right? Like looking to cenobamate, which is an amazing drug and one that we think from an efficacy perspective is pretty much the bar to be achieved. The difference actually happened towards the end, around 400 mg per day dose. There is not a lot more to be done there. At that dose, the overall exposure was about five times less than our initial dose in POWER 1. Is there anything after that or not? We do not know. I think that is why we are taking this prudent way to take a step by step and examining what is really in front of us. Okay. Let's talk about the generalized epilepsy cohort that you're studying there. What do you need to see from that cohort to support further development and also maybe just remind us of the mechanistic justification of the difference versus FOS? Yeah, absolutely. Absolutely. What I would like to see is at least the same, arguably potentially more resolution of seizures than we see in focal sets, right? We gave like the midpoint for the expectations for RADIANT, 40%-60%, so around 50% midpoint. Got to remember all those patients coming to this study, they just had recent seizures. They just failed every standard of care you can imagine. They are on multiple drugs, right? Those are difficult to treat patients to begin with. We would be very happy with that. I am sure the community and those patients would be quite happy with that as well. That would allow us to move forward and potentially start a generalized only study even later this year, as soon as later this year. The mechanism is actually pretty straightforward here, right? I think in the most simplistic way, you don't need to believe a lot to believe that by properly modulating Nav1.6 and Nav1.2 and others, you would be able to stop any seizure, right? There are no seizures without sodium channels. It's as simple as that, right? Like you need to cross a river, there is no bridge, and you don't know how to swim. That is like someone goes, why a military tactic is to implode bridges to stop advancing. That's what we're trying to do here, right? You don't have the bridge, you can't have the action potential being initiated or propagated. That is what we are doing with this drug. There is no way to have a seizure. If you say, well, so why other people do this? They did. That was their first question, right? This is a known mechanism, but everyone had to stop at a point because of tolerability. If our hypothesis is correct, as we believe it is, we're not going to have to stop at that point. It wouldn't matter where the seizure is in the brain or how it started in the brain. Obviously, we have preclinical data. I believe like one year ago or so, we're having a conversation about this. One of the questions you asked, isn't PPR a model for generalized versus focal? We keep going back and forth on these schizophrenic merry-go-rounds where, yes, it's a model of seizures. It's a model of the brain not behaving well. It's a good thing we have proof of concepts in animals and humans on models that cover any type of seizure, any way they get originated. That's why we believe there's a strong scientific rationale here. You've also talked about pursuing pain with this drug. What's your current sort of thinking around that? What's the gating factor? Of course, you have a lot of studies in play here, but just wanted to get your latest thoughts. Yeah. What I can tell by now, without stealing the thunder of like another investor they're going to have in the near future, right, about this is we are very happy with all the preclinical work and early clinical work we did in pain with this family of compounds. We believe at this point in time it is in the best interest of the company to advance other drugs in the family. Maybe I will stop there just to say that we are actively working on the best possible path forward for pain. We're going to have news in the near future. Okay. All right. Let's switch gears to relutrigine. And so the proof of concept study, the drug had demonstrated placebo-adjusted monthly motor seizures reduction of about 46% with about 30% patients becoming seizure-free. That was really impressive data. Now, mechanistically, help us understand how the mechanism allows you to dose higher than other sodium channel blockers without the safety liability here. I guess you've kind of touched upon that a little bit in our discussion earlier, but maybe kind of talk about the efficacy aspect of it as well. Yeah. Yeah. Yeah. Maybe one of the most interesting parts about the EMBOLD study, the first part and what we're doing right now that gets missed is that was it for those patients. There is nothing else you can do. Everything they could have used, they were either using as an anti-seizure medication or being dosed with, or they had to discontinue because of side effects, lack of efficacy, you name it. That was it. When people are like, oh, the placebo effect was very small, and I was like, no kidding, José. Of course, it was very small, right? There is nothing else you can do. Like you are at the maximum there for those patients. The expectation, as you might recall, when we used to be asked, what is the expectation for this study, you'd say 20% is kind of the place there because there is not a lot more, right? When you have like this huge amount of chains possible, you can imagine massive chains. We are really on literally toxic levels of other anti-seizure medications, and there's no additional response. What are you going to do? Our expectations were by giving 10%, 20%, 25% reduction in seizures, that would be quite amazing, right? When you transform 20%-25% reduction in seizures on a patient with SCN2A or 8A, you're increasing the ability for these patients to survive after 18 years of age by five folds. I think very, very few people understand this is the oncology of epilepsy. They are all, unfortunately, diseased by their teenage years, right? Because they're seizing so much. We are very happy with what we're seeing. Completely unexpected to have so much benefits. Now, if you go back to our AS presentation late last year, when they stay on the long run for on that point in time, it was nine months. We are going to be updating the data pretty soon. It was over 70% reduction, right? Now, it is hard to believe that that would even be possible on this population, right? The other point that is worth mentioning is the majority of them are on background sodium channel blockers. It is not that, oh, you know what, you remove something and then you give back. It's gimmicks. It's not gimmicks. This is like true efficacy for these patients, incredibly vulnerable. At that point in time, like we talked about, 33% of these patients being seizure-free, which is mind-blowing on itself. The drug is working and it is doing amazing things for these patients, which is undeniable right now. Our job becomes to create a scale study, which is the current study to actually get regulatory approval on that. We are executing that really well. Like a lot of enrollments in the U.S., particularly, we got a lot of traction from both local patients and patients coming from adjacent countries to participate. We are quite, quite optimistic about the timelines, maybe even beating them here and submitting an NDA next year. What allows us to do as well is to realize how many more patients could be helped by this drug. That is where EMERALD comes to play. Without stealing the thunder, less than a month, we're going to be talking about that. We think that that is where the real opportunity to make a huge change is, right? Like 80%, 90% of patients with disease don't have anything that is effective for them. They try with multiple things. There was a recent obsession in the last 10 years or so on LGS and Dravet because it's the things we could treat. There is this, I would say, fortunate and unfortunate reality in biotech that one that is success in one, everyone goes and starts copying it, but they forget that there's like 80% of the patients still we need, and that's what we are focusing on. Yeah. Yeah. Okay. Maybe just let's continue on the SCN2A and 8A for a second here and talk about the cohort two in the EMBOLD study. What should we expect in terms of, or at least as you've designed the cohort two, how did you power that? What did you power it to show in terms of the response rates compared to what we've seen in your prior study? And what did you assume for the placebo response then? Yeah, absolutely. Absolutely. The expectations, I believe, should be no different, right? A big problem when you actually repeat studies is that we tend to adjust the expectation based on the latest versus based on what we actually had as expectation. The expectation is no different here. It's not because we had more than double of the seizure reduction than we expected that we should just change the bar. The market still needs 20%, 25%. I think that's where we should stay. When powering the involved, I studied the current cohort on the EMBOLD that we're doing. This is the approach we took. We asked, what can go wrong in relation to the previous study and what we expect to go right, taking the definition of right and wrong very loosely. One of the things is that we had very, very little discontinuation. We decided to assume we're going to have significantly higher discontinuation as we go to 80 patients versus 15. We increased that significantly on the assumptions. The other is that placebo was 1.6, as you might recall. We expect to have at least about eight times higher than that. Just in case, right? Keep the response rates around 30% for seizure reduction. When you put that all together, 80 patients is well powered to deliver on this. As you can see, I would argue, we were timid about those assumptions, right? Higher discontinuation rates than expected, higher placebo rates than expected, and smaller effects in terms of the drug than expected. We'll use a few recent studies. If you go through some recent disease studies, placebo has been very, very small placebo response. There is no expectation whatsoever to be that high, but it's better to be safe than sorry on situations like this. Fair. I've gotten the five-minute warning here on the time. I want to skip a little bit further and maybe just talk about the DEE patient population that you intend to study it in and maybe just share any kind of latest thoughts on any specific types of DEEs that you might want to exclude from the study as you're planning to initiate it. If you could comment on SCN2A, LGS, and DS specifically because that's kind of where we get a lot of questions on as well. Yeah. Yeah. When you think about exclusion, right? I look into a study like this. What we don't want to have from a study perspective are one patient without seizures. I know that's quite obvious, but I'm just going to say it. And some of them, and hey, great, and God bless them, have good control. The other is patients who predominantly don't have motor seizures, which is a small but important group of patients. The third one is clustering, right? If we cannot properly count, you cannot properly assess the benefit of the drug. Maybe the more, I would say, gray area here is intolerance to the mechanism to different drugs. Now, we're not looking for immune like classical metabolites induced like intolerance like lamotrigine is the classical there. That's not the kind of thing. Repetitively not being like having like a real issue in terms of exacerbated of side effects, not immune necessarily mediated, which tends to be the more molecule specific than class specific. When you take all of that, that's probably the one population is like 10%, 15% of probably the total markets that we're talking about. Relatively small. Focusing on who we would like to have in this study. We're setting for four accountable motor seizures at baseline. Being on at least one anti-seizure medication, which is being fairly rare actually on those patients. They tend to be on multiple and quite compliant with the diary, quite compliant with diets, quite compliant with medication before. There's a lot of parameters here. I want to make sure they're in. Just like the old days of epilepsy developments where you would just say adults or pediatrics, we believe would serve better the population if the definition is simply as the most recent as Dr. Scheffer and others just published recently, DE is an encephalopathy with an epileptic future in infancy periods, right? This hyper specification that we created throughout the years did not help drug development, did not help patient care. That's really where we're going. We're going to go into details on this event we're going to have soon, I mean, on why these other conditions that on the surface might look like we wouldn't be that effective of a mechanism like relutrigine, why we believe they're going to be quite effective with relutrigine, which is a different way to modulate these channels. Okay. We're almost out of time. I think I will close here. Really appreciate you both taking the time to be with us today and for our listeners for joining. Wonderful. Thank you very much. Thank you so much. Have a good rest of the day. You as well.