Hello, everyone. Today it's my pleasure to be hosting Praxis Precision Medicines. With me today is CEO Marcio Souza. Marcio, how are you doing today? Doing great. Thank you so much for joining us at our annual Jefferies London Healthcare Conference. I'm really excited about your entire neurology pipeline, and let's just get into it. I think top of mind for most investors at this point is ulixacaltamide and essential tremors. So maybe before we get really into the nooks and crannies of the story, let's take a step back and talk about how big is the unmet need in essential tremors and how may ulixacaltamide address this need? Yeah, absolutely, and I appreciate being here, all the interest and the invitation for us to talk about our... I think we're going to try to stay within the four programs we have in the clinic. There's a lot more to the company, as you know, and specifically on ulixacaltamide hydrochloride. That is our lead assets in essential tremor. The idea is to continue that in other tremor disorders upon what we expect to be positive results early next year for the two phase III programs. The market itself, it's actually super interesting in a sense that when you start talking about essential tremor, I particularly haven't paid much attention before Praxis. Since like the last five years or so that I've been deeply involved with essential tremor, the number of individuals I actually knew or families that have been suffering from and withdrawing from society and withdrawing from different functions on their lives or making choices that are less than ideal for their skills is incredible. When you look into hard numbers on the U.S. markets, we did probably the most comprehensive work ever on epidemiology. We tend to look into the markets on everyone who has essential tremor and then on people who would benefit from ulixacaltamides at the point of launch and in the years to come. That ended up being about 7 million patients in the U.S. total. Very, very similar numbers outside of the U.S., but just use one that is very well understood. About two to 3 million patients that at any given point in time are seeking treatment. The second layer of how interesting this is, the conversation with their neurologists, the conversation with their physicians is about treatments, is how to actually improve their life. It's very little about what do I have and what's the condition. About 60% or so of those patients are from familial cases. Unfortunately, many, many genes. So one approach there to modulate the gene would be incredibly difficult. But the family members normally bring, and we, through our pre-screening from this study, which was incredibly large, were able to understand the number of other family members that are affected. It's larger than we expected. I guess we should be expecting to be large, but we were not really that confident at that point in time. So when you look into this disruption on the life of this patient's by losing function, because that's what it actually is, right? Tremor is just what we can see, but what actually happens with tremor is losing function every single day. And knowing that there are two, three, four, five individuals in your family losing function similarly is quite meaningful. So the unmet need is undeniable. The need for treatment is undeniable. To give you maybe, and to close this part of the topic, the last update we gave about a quarter ago was that the spontaneous and referred interest to our study was about 75,000 patients. And I can update you right now and say that as of the last few weeks, we got to over 100,000 patients referred to the trial. Just let like a number like that sink in, right? On people that are going above and beyond to participate in a study that they know is blinded, they know there's a chance to receive placebo, and crossing the line really in attempting to get something in the United States alone, because the study is only in the U.S., it was quite validating to the epidemiology and validating of the needs. Amazing. And maybe now getting into the potential treatment you have, ulixacaltamide. First, there's the T-type calcium channel inhibitors. There's a number of them that have been studied. Quickly, kind of how is ulixacaltamide differentiated from some of the other ones? Yeah, so there were two other drugs that were attempted as T-type calcium channel blockers, modulators. I think we can be a little bit liberal on how we describe them. I think the fundamental difference, right, I would say when you are screening for those drugs and for ulixacaltamide, as we call, they're actually pretty similar on the ability to modulate in animals. The problem is when we bring to the big animals like us, and there has to be enough drug in the brain, and it has to do what we are expecting it to do, that is block this channel on the anatomic place that we're expecting that to happen with the level of occupancy that is expected to. And I can go on and on. And in every single one of those aspects, ulixacaltamide is superior. It was not completely unexpected from our perspective that we would be ahead every single time that we look into that. It's not to say that there wouldn't be other ways to maybe reformulate or maybe deliver differently, but it's incredibly difficult for other drugs when they are inferior on so many basic aspects to actually succeed. So then maybe diving into it, what are kind of the key phase II data for ulixacaltamide in Essential1 and prior studies? Yeah, so the first one was even before a phase II, and I would say we did a very, which I believe to be quite clever, translational study, right? We know what happens with these channels in the thalamus through a biomarker study, and we knew there was alteration exactly there. So we got two information, anatomical and biomarker information when we did that. So we checked that box. And then on the two phase II studies that we ran before the phase III studies that we're doing right now, and maybe taking a step back is being the first in a field that really has not been a lot done. There were a number of questions we had to answer on the phase II, like endpoints, selection, type of population, how long the trial should be, you name it. I believe we quite beautifully answered all of them, right? What we know is 60 mg per day of ulixacaltamide is the ideal dose. We had an agreement with the agency, with the FDA that that's the dose we're caring for. That's quite important. It's also quite important that was not the top dose. There was really no difference. It was not inferior to the top dose, but we have a lot of the safety to maneuver there. The drug was pretty safe. We're seeing quite important changes on the function, right? Because it goes back to what matters is function of these patients. Like I drink a lot of coffee, as a lot of you know, and the ability to just hold your cup and actually drink and dress in the morning and brush your teeth, all of those things that most of us take for granted are activities that patients with essential tremor, moderate to severe or severe patients cannot do. So just that ability to be able to do that, that we're bringing back to patients is incredibly important. That's what we're seeing on the phase II, very encouraging. And that's what we are aiming to see on the two phase IIIs as well. So maybe let's just get into the phase III Essential3 program. Maybe remind us key design features between Study 1 and Study 2 and how is enrollment proceeding at this point? Yeah, so Study 1 and Study 2, as we call them, I know not very creative there, so my apologies for the simple names. They are part of the Essential3 program. We made a few decisions based on what we learned before on this problem. One of them, an incredibly ambitious decision is that we'd enroll both studies in parallel. But not only in parallel, but through the same recruiting protocol. So patients actually get randomized to these studies, which is incredibly unique here. So when you get, let's say, three patients, two go to Study 1, one goes to Study 2. That allows for two major things that are incredibly important. One is the pace. The second is those groups are very, very similar. They are randomized by the same stratification factor to Study 1 or Study 2. But the most important thing, in my view, is that the patients on the study don't know which study they're in. So it allows us for comparisons that would not be possible in any other setting. Now, study one from a design perspective is a one-to-one parallel group, 12 weeks in duration, where patients receive either drug, ulixacaltamide daily, 60 mg, or placebo. And study two is a standard responder, standard responder randomized withdrawal. So eight weeks on drug, and then for the responders, one-to-one randomized to stay on drug or to go on placebo. But to go back to the difference is in virtually any randomized withdrawal study, patients know they're on drug at the beginning. So you always have a little amplification of the effects, which makes it a little bit harder to actually discern afterwards. And that is a little bit of the risk. So we removed that. We took that risk off the table. But it also allows for comparison throughout the study, which strengthens the overall body of evidence when approaching a regulator like the FDA. We'd be remiss to forget that you have de-risking data both on the parallel study side and the withdrawal side from your phase II. Correct. So the previous phase II, the latest phase II, essential one, was a parallel group design, eight weeks, not 12 weeks. What we tend to see is patients stay longer. They amplify the effects. We did not account for that when we were powering the study. We took a little conservative approach and we ran two separate small studies, randomized withdrawal. I think the randomized withdrawal, the prevailing opinion, I would say right now, is that that study is very de-risked, because when you look into the previous data, patients do lose all the effects and a bit more when you remove the drug. So again, biologically, it is very de-risked and fundamentally from a trial perspective. That is the package for the submission of the NDA that we discussed at the end of phase II meeting. So that is why as well they are reading at about the same time. Great. And then, just quickly, interim looking around for mid-1Q of next year. Yeah, yeah. We have made a decision at the beginning of the study to include. We had a discussion with the agency and to include an option for an interim analysis for Study 1. Study 2 does not make sense for an interim analysis, and we can discuss that why. And the reason being at that point in time was no other drug has run so far, other than us, a phase III study in essential tremor. So while we learn a lot from phase II, I think we have to remain humble, may I say, in terms of potential things that happen throughout the course of a phase III that is four times larger than the previous study, right? So we could have just more variability, just more difficulty on keeping patients on drug, you name it, many things. It ended up that as we monitored the study throughout, that was not the case. Everything was kind of matching like clockwork, the parameters that we were expecting. But a competitive drug read out early in the year, and one of the elements that they mentioned on the disclosure that was unexpected to us is that they had a little bit more placebo effects. Placebo is not problematic in essential tremor, differently than other CNS conditions. It's actually pretty small, pretty stable throughout visits. But out of caution, abundant of caution, may I say, we decided that for the costs, and I mean statistical costs, time costs, and the benefits on the other sides, that was appropriate. So it's skewed towards sample size re-estimation, which allows us to, if we're wrong by a little bit, we can increase the sample size, regain the original power of the study, and just read out the study. People normally don't do that because attracting patients to a study is incredibly difficult, right, in general. But it has not been a problem with us like whatsoever. I mentioned the top of the funnel, like 100,000 plus patients. Of course, a lot of them cannot participate in studies for multiple reasons. But even when you look downstream in terms of the number of patients who have moderate to severe, don't have any comorbid conditions, so on and so forth, it's still significantly higher than anyone has ever seen. So the confidence on actually completing the study was incredibly high, and the ability to actually de-risk was incredibly high as well. So it made a lot of sense for us to conduct the analysis, which is forthcoming in Q1. Great. Well, we're really looking forward to that, but we're also looking forward to some of your other assets, such as vormatrigine, which is going to have a readout for the Radiant trial in the first half of next year. Maybe we could get a little bit into what is the excitement of that asset in epilepsy. You ran a PPR study and have QEEG data for vormatrigine. Kind of what are the key data points we have currently for that compound, and why does it make you so excited, both in focal and generalized? Yeah, so vormatrigine, it's a curious compound, right? I think when we've done the original in vivo work and in epilepsy, in vivo work is incredibly predictive, right, in humans. I think we all thought it was wrong, to be perfectly honest. This is the most potent drug ever developed in epilepsy, in developments or previously developed. You can double-check the numbers. Others definitely tried to. And at the same time, it has the largest therapeutic index of a drug in this class. So when you put those things together, you got to doubt that that's actually real. And I think that that was the first thing we did. And then we moved forward, completed all the preclinical work, all the tox work, everything related there, and done all the pharmacology work. Can we get to exposures? Can we get to exposures in the brain, like your typical, and checking all those boxes? At that time, we concluded the work. The company was in a very different capital situation, right? So one could argue, and I think people argued with us, just go straight and run a focal onset seizure study. It's going to be incredibly successful. But we chose to take an extra step and to look into patients with epilepsy, but we could measure in a very simple way by stimulating them if they were sensitive to photostimulation and look at what happened when you give the drug. And this study being done like about 30 times before, every single drug that was positive in this study ended up having very good efficacy data in focal or sometimes in generalized epilepsy. So we knew there was a good predictive value there from a positive perspective. What we were not expecting is to get all of them to respond, because it has not been seen before, but it does fit the overall hypothesis for the drug, so we have three studies running right now. The one that you mentioned is Radiant. It's reading out the first half of next year. As the gods wanted, it's now very close to the interim, very close to study one and study two, so create even more excitement around us, like all these catalysts, but it is the most exciting drug I ever seen in epilepsy, which is incredible. Awesome. And I also wanted to pick your brain a little bit. I think naturally or not, investors often focus a lot on seizure-related efficacy, especially when it comes to focal benchmarking, et cetera. But what are some important factors for physicians prescribing ASMs other than seizure-related efficacy that vormatrigine may be able to provide? Yeah. So when you talk to physicians, and not only epilepsy experts, but the general neurologists and very large neurology-inclined practices that are multifactorial in terms of how they are composed, efficacy is quite important, of course, right? Every seizure can end up being the last seizure that a patient has. It's incredibly important to stop it. Safety has been the limiting factor. Brakes are stuck. So you try to accelerate more, but you can't. That's a little problem with the, a big problem with the total. But once we solve that part of the equation, every single time it comes, yeah, but how well these drugs work, right? There are drugs in the market right now that work pretty well. Cenobamate is an incredible drug and helps a lot of patients, but takes so long to get patients to therapeutic levels, about 12 weeks or so, that unfortunately a lot of them don't have. They're going to have breakthrough seizures in between. And the tendency from a prescribing neurologist is to actually switch the drug. So they never actually got the opportunity. The other one is a drug that's given once a day, with or without food, doesn't matter the time of the day, and that you have therapeutic levels at day one does not exist today. So for that alone, one could argue it would be $800 million to a $1 billion drug without better efficacy. When you put the better efficacy together, then the sky's a little bit off the limits here. Amazing. And that's two incredible assets. But I'm just as excited about relutrigine and elsunersen as those assets. I kind of think of them together because they're both for DEEs. And feel free to touch base on both of them. But maybe first, what's the registrational path from this point for relutrigine, SCN2A and SCN8A DEEs? Yeah. So we just read out a little bit over, I guess, two months ago, the phase II with relutrigine. It was PRAX-562. What we were expecting is what we've seen. I think sometimes one gets a little bit scared of creating the expectation of a drug being what you really expect it to be. But when you started seeing patients actually having no seizures at all, right? So 33% of the patients on the study had a period longer than 28 days without a single motor seizure. So I encouraged all of you to actually ask physicians that treat these patients and ask what is the longest they've seen these patients is stable that were seizing at least eight times per month. And the at least was about eight times lower than the median that they were seizing at that point in time. So the baseline was just the entry criteria, but they were actually seizing significantly more than that to go to zero. A patient with 100 seizures in a month go to zero and stay at zero. That was exactly what we were expecting if we believe the titration and all the work we're doing. But biology has always played tricks on us. So we're being a little bit careful on how it looked in general, but quite fantastic. We did not wait to start the second cohorts. As we were seeing zeros, we had to attribute that to drugs despite the fact that the trial was double-blinded. So we decided to take a risk and start the recruitment of cohorts. I can tell the interest in patients in screening right now is being very high. We guided for 2026 the readouts and submission of the NDA for that drug in 2A and 8A. But it does not end there, right? There's about 100,000 patients in the U.S. with other DEEs. I'm going to call that all DEEs for the sake of the arguments that can and should benefit from this mechanism from a drug like relutrigine. That's what physicians have been asking us to do. So we are starting a study early in the year called Emerald that's going to be addressing that part of the markets. So not to get distracted, we're going to get first 2A and 8A, bring that to registration as we complete Emerald. But the overall potential for the drug is really to address 100,000 patients plus in the U.S. with DEEs. It has not been done before. And we're incredibly excited about the value to patients, value to shareholders, and all of us on that journey. And then maybe in the next 30 seconds to talk about the ASOs. So we have four ASOs right now. Everything I just talked about small molecules. We have a different platform for ASOs. The first of them is elsunersen. We had a phase I-B on patients with SCN2A DEE. There's like a very severe gain of function on the Nav1.2 coding gene. Tremendous results. They're all incredibly refractory. Maximally exposed to sodium channel blockers, quite sedated because of that as well, and with a lot of other side effects. So more than 40% reduction in seizures over the four months, quite constant from month one. And as many or more, 50% more increase in the number of days without seizures. So imagine a parent when a kid is having seizures every single day to have several days without what brings to their life. So we're dosing a second cohort right now. And in the beginning of the year, we expect to start running the phase II, III that would be registrational for that drug. There are three more drugs. They were declaring candidates and going to GLP tox early in the year. So by the end of next year, there's going to be a little bit more for us to discuss as well. Amazing. Well, thank you, Marcio, so much for joining us. I'm so excited about the four exciting drugs we have visibility into right now and wish you the.