Praxis Precision Medicines Inc Aktie

Great. So welcome, everyone. It's my pleasure to introduce the President and CEO, Marcio Souza; and the CFO, Tim Kelly, of Praxis Precision Medicines. My name is Kevin Strang, I'm one of the biotech analysts at Goldman Sachs. And yes, so welcome.

To start us off, maybe for those that are kind of newer to the story, would you mind giving a brief introduction and maybe what you view as your core competencies and philosophy as a company?

Yes, absolutely. I appreciate it. I appreciate the invitation and being here today. I'm Marcio Souza; and Tim Kelly, our CFO, is here with us.

I think what we're trying to do right now, right, and arguably done part of this and going to be hopefully finalizing the next part, and then comes the next and the next and so on, is to address like a fairly large number of markets in CNS.

When you think about like essential tremor, for example, which is our arguably largest part of this, has really been nothing. And maybe Tim can talk a little bit about the size of the market and I'll go back and talk a little bit about the science and so on. And everything else, I would say, fades, when you think about ET. But, yes.

So when we talk about essential tremor, it is one of the largest movement disorders, roughly -- a prevalence of roughly 7 million patients in the U.S., about 2% to 3% of the population. And there's never been a drug designed for this population, which is staggering given the size of it.

Another movement disorder, much better known, is Parkinson's, that has a prevalence of about 1 million. So you get a sense of just how large the essential tremor opportunity is. While there's a prevalence of 7 million, our initially addressable market is about 2 million. And we get to that number from a longitudinal claims analysis that we did a few years ago that the conclusion out of that was there's about 1 million patients currently on treatment, and propranolol is the only approved drug, they're taking a number of other things off label. And then an additional 1 million patients who have tried treatment but come off of it.

And so when we look at as we're launching, we're not going after the full 7 million. We think there's definitely opportunity down the road to bring market share to that group, but initially focused on those 2 million patients who are currently substandardly treated or have tried something and gone off. And then there's an additional about 200,000 patients who are diagnosed every year as well, particularly as this is an aging population and it is a disease that progresses with age as well. So we talk about 2% to 3% of the broader population, it gets to be about 6% to 8% of the 60-plus population also.

There's quite a lot for us to focus on and target. And what I think we'll go through in the next few minutes is the strength of our drug ulixacaltamide to address this market. We are in a phase right now where that's under NDA review with the agency. And so a lot of what we're doing right now within the company is to prepare for the launch and the upcoming PDUFA date in late January of next year.

I think why I wanted to talk a little bit about the numbers, right, and get Tim to speak about that is we normally start with like the studies and like the FDA process and things like that. But in a sense, the reality is there is no other market where you have like 2 million, 3 million, I think we've been putting this on the lower end, of 2 million or 3 million patients, and with basically absolutely nothing for those patients.

I think from a market opportunity perspective, it is completely different than any other market, when you think about like competency, as you said, we pride ourselves on really thinking very deeply about new markets, as you probably have just heard, not only on the understanding of the next phase, but before that. So there are reasons why on a market that large, no one but us up to this point succeeded. And we've done our relationships with the agency and making sure at moments like now, particularly in drug development, I think we have to be very thoughtful about how we engage with the FDA and with the other entities, on top of all the work.

Tim just mentioned about that we've done with physicians and understanding the market and so on. We have very deep understanding of the payer, like in how they view the drug, and therefore, like what kind of process and particularly support for these patients you need to put in place. But there is no place we -- I would look into that does not result into like very, very large.

And I think sometimes when we put numbers like $10 billion peak revenue for this drug, it sounds, for some people, a little bit absurd because we just haven't had a lot of $10 billion drugs. But if you actually take the very simple mathematical way with like noncompetitors, millions of patients, like a drug that is very clearly effective and safe for these patients, actually becomes in a sense a conservative number, if I may.

Got it. So sort of to bookend that, 2 million is somewhat of a conservative number in that they've already been diagnosed and treated and are either currently on therapy or have come off. And so I guess for ulixacaltamide, can you talk at a high level about how you can address sort of this unmet need for those patients, the efficacy benefit that you're seeing? I guess we can start there.

Yes, absolutely. So there are very few times, I think, in drug development, particularly when you are looking for a new indication, that you not only have like a large indication, as you just talked about, but what do you measure and what patients actually are asking for the same thing, right? So when we're talking -- you can imagine we talk to thousands of patients at this point in time, including a very recent survey we put a little bit in our corporate deck, really trying to understand what do you expect from the drug, number one, and how does this condition affect you.

Because it's so common, I think one of the biggest features, unfortunately, I may say, of essential tremor is that people just try to hide. As you go through life, the vast majority of the patients start having symptoms while they're teenagers. And that's one of the misconcepts, like most people think about like an old people disease, but it's actually very early life that it starts. 70% of them have family members. So that's normally second or third or fourth person in the family has it.

But then it does slowly progress on losing functions. And the reason why that's important is it's an increasing disability disease, right, where you are like feeling some internal tremor and then a lot more external. And then like you can't write very well, and you progress to full blown not being able to do anything, like no dressing, no eating, no -- of course, never leaving the house to socialize and things like that.

So the FDA gave us a very strong advice a few years back that they had no interest in a sense on measuring the tremor itself. Very wise. And at the time, we didn't think was so wise, but now we realize why it works. Because it varies a lot throughout the day. But what it does not vary is the impact in life. Like it would be incredibly difficult for those patients to be like here and like drinking their coffee as we are, or even having the breakfast as you just -- as you had this morning. That's not possible for them.

Compound that with age, right, and then you see like this really big problem with an aging population as we have in the U.S. The results of the Essential3 program, we had anywhere between like, I would say, the mean on about 5 functions on the ADL restored, to up the way to 0, like meaning the ADL goes to 0, no function effect. Right?

When you look to the American Academy of Neurology, we had the plenary meeting for clinical research, over 20% of the patients had more than 12 restored. So when you put that together when we're talking about the size of the market, this is not a small change. Even if -- I would argue that even if it was small, it would be quite important for to judge what's important for our patient. So those are very large change on their lives every single day, that gives independence in a sense to some of those patients.

Got it. That's helpful. And you've highlighted sort of the distinction between tolerability and safety when it comes to the profile of the drug. Can you characterize the tolerability profile that you're seeing?

Yes. So the drug acts on an incredibly important part of the brain, primarily, right on the thalamus. And I think what we learned as well is there are certain patients, like about 70% of the patients, you can go very quickly to maximal efficacy and they tolerate the drug really well.

But for about 30% of the patients, it's a little bit too much to go that fast. Of course, we could just say, let's ignore like this 30% or so, because with a market of a multimillion number of patients in the U.S., from an overall like financial perspective, irrelevant. But that's not how we think, right? Every single one of those patient's important to have the drug. So why we didn't have any safety concerns? And I think it's incredibly important to highlight this when you're studying a population that the average age is on their 70s, in our study was 68, you're concerned about major like safety issues, right, like hepatic, renal, like you name it, that we don't have any of that.

But we did have a lot of dizziness that led to discontinuation, on about like 30% of the patients. When you take a step back from that, our understanding very clearly now is that if you keep the patients for a few more days, they tend to basically stay so it goes away, the dizziness. One of the conversations we had with the FDA, what they proposed for us, that we kind of try to come up with a label that, and analysis supporting the label, of course, that would allow for a lower number of patients to have discontinue with dizziness. We did propose something for them based on the Phase II, where discontinuation was about 10%. So we have that knowledge. We're able to propose. And it's actually incredibly simple, at least a priori, where you keep the patients for a longer period of time at 20 milligrams and they tend to resolve.

So we give them the opportunity to, one, not to have like the dizziness that leads to discontinuation on this. I'm going to call it small just because it's a minority of the patients, a small part of the patients. And at the same time, give the best possible benefits once they continue on the drug. So again, a great outcome in general, the way we see it.

And sort of where would you say you are in terms of that strategy, your confidence in being able to implement that? And then what flexibility do doctors have in the real world on sort of holding...

Yes. I'm going to start by the last part there, Kevin, if that's okay. The irony is that when we present this to a very large number of doctors, they say, "Oh, this is just like every drug I have every single day in neurology, and I'm just going to figure that out and I'm going to titrate them to effect when they need to." So they were never the actual issue here, and doctors are going to do what doctors do when the drug is available in the market.

I think it's important as well that we have as much data to inform, in the label, to inform those prescriptions and to inform the proper use. And the combination of the Phase II, as I just mentioned, understanding how the tolerability is significantly better if you just slow down on some of those patients, with the FDA really, I would say, supporting at this point in time, including that in the label, of course, it's going to be a matter of label review in the coming weeks as we're entering that phase with the agency. But it seems to be a very good setup right now.

One other thing I might layer in, we talk to physicians as well. And the neurologist population in particular, they're very aware of the disease, and also that they have been able to -- not been able to treat their patients efficiently with the existing drugs, propranolol being the only thing that's approved. But the other things that they're using, it's not enough for what they want to do to provide their patients some relief. And so a lot of awareness about the disease and a lot of interest in ulixacaltamide as a therapy for these patients as well.

Got it. And I want to talk about what you're assuming for sort of long-term persistence on the drug in the real world setting. What are your assumptions going to that? What data points do you have in how long patients could actually stay on this drug? Is there sort of like a benefit threshold that they need? Just how do you think about that? Because I assume it's a factor going into your $10 billion peak assumption.

It is. Well, take a step back here as well, which I find it super interesting. When you go back to these studies, right, and the way we've done these studies was understanding that no one succeeded before, what were the key features we needed here. And we made it incredibly simple for our patients to come in to the study, which, at the same time, made it incredibly easy for them to leave the study. So that was one factor here.

When you look into the number of patients right now on drug, right? And the study ended, of course, last year. We reported the results [Technical Difficulty] was before, it's pretty much everyone that completed. Like of course, there's some life goes on, again, with age and so on. But it's a very, very high number of patients that were on the drug at that point in time are still on the drug right now. We have patients for years now receiving ulixacaltamide hydrochloride, which is, in our view, incredible.

But maybe quite importantly as well, we really haven't had like discontinuations that, due to lack of effort, to -- directly to your point, right? But whether or not they were for lack of efficacy and then the patient then reports, of course, they cannot attest to that. But in a lot of studies, you see this, right, like lack of efficacy as one of the main reasons. So the patients really see the effect. In our rather limited but important open-label extension from the previous study, we see an increase in their response as they stay for 3 more months at the end of this when we measured that, which is very encouraging.

Of course, we're talking here about the progressive disease on their 70s. The fact that we are seeing multiple functions regained is nothing short of like fantastic, I would say. But the fact that they see that response, they tolerate the drug well after the discussion we just had about how to get to that point, and they stay for multiple years. It's fantastic.

Are we accounting for any of that on the forecast? No. Because I think the -- again, I said simple math before, but if you actually go and do the simple math, this is not $10 billion, right? It's probably more like $20 billion. So we are taking a conservative approach. And I know it sounds oxymoronic to say conservative and $10 billion on the same sentence, but it is.

So we're taking the clinical study discontinuation, right, as kind of the worst case that we've seen so far, even knowing that we can do better than that. That was without support. We're using the lower end of what the pricing can be. Maybe even less than the lower end, one could argue here, and in a slower curve to get there.

In the recent work that Tim mentioned we did with a few thousand physicians in the U.S., we haven't done a lot of work in the fields, as you know, in terms of like we didn't have like a large MSL group and going there and exchanging scientific information with these physicians. It was incredible to see, one, the level of awareness, unaided, right, things that we haven't read it out to them, so how much they know.

But then the second, that was the most fantastic for us, was their day-of-launch intention to prescribe is about 2.5x our peak intention to prescribe expected. So I think we're in a very good territory when we think about the forecast in general.

Now your next question could be, do you actually have supply for all of this, right? And that's something we've always been very careful on building the inventory, to make sure we can, on one would call like a best case scenario. We're not going to inflate launch expectations. Quite the opposite. I think we have to be responsible on what we are seeing. But it is, I would say, using all of this, as you can see, we know very deeply this market, we're very happy with how things are shaping up.

Got it. I just wanted to do a quick question before we get to that commercial aspect. But just to bookend the label and how you're thinking about it, where do you anticipate from now on the most discussion with the FDA? And I guess, just how should investors think about the titration language, warnings, contraindications? Like what should they be looking for in the label? What are your expectations?

Yes. So think about it like Page 1 or Section 1. There is no expectation for contraindications here. So I'm going to be clear there. The warning that you would expect is the things we just talked about, right? Yes, people can get dizzy. It's important that they discuss that with their health care professional particularly, in general.

I think the bottom line here of this indication as well, of course, we'd never be able to speak for the FDA, but we've been multiple times now in multiple conversations with them throughout this program, and December last year, after reviewing the final results, they granted us Breakthrough Designation. I think that point is important because all the safety, tolerability, the efficacy were there. It's incredibly hard for someone to look into the clinical results of this study, particularly the level of detail the agency has, and say, it's not bringing benefit for the patients.

So then you turn to the other side and say, "Okay, is it harming patients, right, in any possible way?" Like normally the major organ systems and particularly liver, here. And the answer is no. So the benefit-risk has been and will continue to be, in our view, quite positive.

So the discussions now that we are entering, as just said, pretty soon in terms of labeling, will likely focus on proper use. And we know because we asked for the advice from the agency and they told us that they don't want to trade off efficacy for tolerability. So they think that we can figure it out, both of them together. And the proposal at that point in time is for a second titration, right? The original titration, the titration on the label is 20-40-60, 1 week apart, milligrams per day. And the alternative one is 20 milligrams, like staying for a long time.

The good news there is that it's not that you have zero efficacy at 20 mg. So it's not something that you're just having anything. And when you switch to 40 mg, you see basically the top of the efficacy there as well. So it's actually a pretty good benefit-risk for the patients in general. We are very optimistic about it.

Great. And you talked about pricing briefly. I think you've talked about maybe $50,000 as sort of an annual target price. Is that a target? Could that be a floor? And sort of what analogs are you putting into that?

Yes. So it is -- not going to be disingenuous here, I just said that it's a space there, right? It's more of a floor, the way we're looking. And the reason why is like we did a lot of analog work, number one. If you look into the initial population, right, what you're going for, the kind of benefits the drug gives, but particularly what payers are telling us, because I think at the end of the day, that is going to be the how they have ramped it up, I think there is basically no resistance or elasticity as we call between, let's call, $50,000 and $100,000 or even maybe a little bit more than that.

So then we have to ask ourselves, what is the best for the patient and what is the best for the company and our shareholders? And it's probably the number in between, and the kind of service that we believe we should be giving here, particularly like medical education in terms of proper use of the drug. There's no expectation to have anything more complex than just the label. So there's no REMS expectation, there's no mandatory medication guides or things like that. But we do believe that we should be educating. Those things cost money as well, so we have to support. And then the next development. So I think to guide between $50,000 and $100,000 is probably the place to be.

Get some analogs too when we look at the tardive dyskinesia market, so a little bit smaller, but it is a movement disorder. There are a couple of players in that space and the price is in the low 6 figures. So it does give an analog. What we're talking about is a price that recognizes the value of the drug so we can support patients, but also gives a floor for where we can price.

Great. And on the commercial aspect and having [ favorable ] pricing, you talked about potential step-through requirements for propranolol, which is the only FDA-approved drug. Can you talk about your expectations for how that will work? And then even though it is the only FDA-approved drug, not every patient is on it. How does that dynamic work in terms of getting access to the drug?

Yes. So I think when we're planning for uptake execution, it is more conservative for us to expect step-through with propranolol and then work with the upside if there's not as much there, so rather than be surprised by it. With that, we don't expect much friction there.

So one of the issues with propranolol, it's a beta blocker. Given the age of this population, about half of them are contraindicated from it from the beginning.

And then the other aspect of it is a number of them have already tried it. So what we might expect is maybe there is some type of requirement for how they tried it in the last 3 years. And I think a part of what we're looking at in terms of our commercial execution and rollout is how do we use data and systems as well to help support things like prior authorization and step-through and accelerate that aspect of the process. And it would also be part of what our medical communication and information is as well, that we can support the physicians as they're going through this with all that's required there. So that if propranolol is required, we do that. But we get patients onto the drug that can really help them, which ulixacaltamide hydrochloride.

We'll give you like 2 data points there. So one, in our forecast, we assumed everyone would step through propranolol. So we'll think about how conservative we are being there. And then Tim just mentioned half of them cannot medically even do that.

And the second is we went to the private payers, right, and we asked like, we're going to enforce any restrictions, and here is the population, expecting for, well, that all of them are going to say yes at day 1. It was less than half that said yes to that, understanding the population, right? We're talking about numbers, like think about the like UnitedHealthcare [ lives ], there's like a lot of those patients, for example, which was surprising, to be honest. And I think it's just looking into how much utilization of the system these patients end up having with ancillary support and then, ultimately, really needing a lot of care and what the drug can give. Delaying the treatment is probably not wise on a drug that gives its maximum treatment.

It's starting around 2 weeks. So it's like incredibly fast to get there as well and to help these patients. So it was another interesting potentially upside here in general.

Sort of on the commercial readiness front, you've talked about maximizing your investment upfront in terms of maximizing the commercial opportunity. So can you talk about that investment, what that entails in terms of sales force and sort of education perspective? I know you shared some awareness campaigns. And can you talk about where you are today versus where you want to be in January?

Yes. So I would say we're more than halfway through it. Our launch readiness expectation is in Q4. Like some place in Q4, I'm not going to give the exact number. So we're not trying to be ready by January -- like the end of January as the PDUFA, but actually by relatively early in the fourth quarter. So we have to be pretty advanced right now in order to be there.

One, things can always be accelerated with the agency. I know we normally think on the other direction, but we need to be ready for the both directions. And the second is just making sure we understand this market as much as possible.

We start with a base of like over 217,000 patients that were in our database, right? That's where we're starting from. And those all have physicians linked to them. And then as Tim just mentioned, we just refreshed the claims data sets, which we were able to like really understand who in the last 12 months, 24 months, 36 months, actually seeing one of those patients was the largest concentration.

When you put all of that together, it is about 13,000 to 15,000 targets in the U.S. are like accounts that we want to cover. When you back-calculate all of those things, we are about like 200 to 300 sales reps to cover that. I think most companies would start at 200. And I think we're making a decision that we'll start with 300 because then we can cover everything we just talked about: the potential upside [Technical Difficulty] middle of the country, particularly that is [Technical Difficulty] [ budget ], so there's a lot of large PCP practice covering the space for neurologists, and they need attention as well.

And as we discussed as well, we want basically no patient left behind in a sense. So we want to make sure the physician prescribing understands the drug and can guide the patients. So the wave one of the launch is going to be neurologists and the top decile for PCPs on this disease.

Yes. I think we're fortunate with the balance sheet that we have right now. We can invest heavily upfront into the commercial launch.

The other thing I would say is ulixa in January is our second launch over the next 3 quarters. So we'll have a little bit of time maybe to get relutrigine, but we have that coming at the end of September as well. So there's a lot of activity internally right now.

That was my next question actually, because I know we can talk about that all day, but moving to relutrigine. This is actually potentially your first approved drug in -- with a September PDUFA date. Can you talk about the opportunity in the initial genetic indication and then how you're preparing commercially for that? And then we can move on to potentially the broader opportunity.

So the SCN2A and 8A, which is intended to be like the first approval here coming up, September, I think my guess is on the 25th, just because the 27th is a weekend. But you can tell me I'm wrong when we get there and they actually do on Monday instead of on Friday. We'll see. We are preparing a next month launch readiness date for us. We want to be launch-ready in a few weeks. It's progressing incredibly well with the FDA.

I think the reason why we focus a lot on ET is really people not even grasped the surface on ET. And I think it's a little easier on relutrigine to talk about that. The first launch itself, and we should always think about the first indications over like billions of dollars in potential revenue here for 2 reasons, right? So one, 5,000 to 10,000 patients in the U.S., all of them need better drugs. Like this is not a matter of like who is doing well, who is not doing well. No one is doing well on this condition. It's going to be the first approved drug for indication ever, once again, just like we're discussing before.

And when you go back again to payers and so on, then we're talking about not really having an upper limit. And then we're just wanting to understand what maximize access here in general. The choice we took was to actually cover a little bit more than the centers of excellence, I'm going to call, at time of launch. So going to hear us talking more and more about numbers, but you could easily cover this market with about like 30 or so sales, like reps or personnel in the field and maybe like about 1/3 of that in MSLs.

We're probably going to go a little bit on the higher end. As you can see, this is thematically how we're going for this. We're not believers that every 3 or 6 months, just say, I'm going to increase, I'm going to increase, chasing the demand, is the appropriate way to launch drugs anymore. But rather to get the best possible experience from the get-go, maximize the launch.

And remember, we have EMERALD coming up in Q4 as a result, which expands the indication about 10 to 20-fold, depending on how we want to see here. We're incredibly confident about the clinical profile and what we are seeing from a blinded view on that study and what we're getting from the patients who already rolled out to the open-label extension.

So when you consider we should never launch for the second indication, but I think we have to be ready for the fact that physicians are going to feel confident and they're going to start wanting to have conversations with the MSLs and so on about that. And we need to be there for them when they want to talk about it.

Got it. And can you share what you're seeing in a blinded fashion that gives you confidence?

Yes. I think there's a -- I'm going to call a shape of the distribution that gives you more or less confidence. We always have to be incredibly careful about blinded review, like I think we've all been burned before. I have, for sure. But there are certain distributions, I would call, that they are just clinically impossible on a population that is so refractory. So the more to like very high response rates, I would say, in a large number of patients in the study, the more confident one should feel, particularly when that is associated with very good safety, as we are seeing on this study.

We enrolled more than we're expecting initially on 160 patients here. I think we talked about it. We use very, very high-quality pediatric site with a pediatric condition. We wanted to make sure we have those patients there. And we wanted to make sure as well that there's no overrepresentation of some cohorts, particularly the ones we know that is efficacy-ready, like 2A and 8A, and we accomplished that. And I would say having -- basically looking to this every day for many weeks, that I'm as confident as one can get about what we are seeing.

And is there anything in terms of the -- like how do you think about execution risk from going from that concentrated population to a more genetically diverse population?

Yes. So the good news here, twofold. So one, prescribers are the same, right? So when you're talking about promotionally about 2A and 8A, if they have a question, we can get that to our medical team to answer the questions about the broader. So we are right in front of them, which makes it incredibly easy. They are already coming to us and actually asking questions right now.

And then on the second, of course, we're going to be pricing this thinking about 2A and 8A and. And what we are hearing from payers in general is that we probably have 2 to 3 years to make adjustments if we need to. So it allows for that very successful financial ramp on the following like 3 to 4 -- 2, 3 years here without having to start considering price adjustments and things like that.

So when you're looking for recent price on the rare disease space on drugs that actually have competitors, which is not the case here, we're talking about anywhere between like $450,000 to $650,000 per patient per year. I think that's a good place to start here as well.

Great. And I want to touch very briefly, you had a recent update, vormatrigine in focal onset seizures. Can you just -- what can you say about that at this point in terms of that program and where do you go from here?

Absolutely. So we just had, yes, the results from the POWER1 study last week for vormatrigine. I think a couple like good news and a couple of bad news there, right? So the bad news is that it's not the profile we wanted for that population. So we did not meet the expectation from the seizure reduction that we wanted. There was positive on the responder rate, on the 50%. So that's one of the good news.

I think there's a lot of other good news here, right? So we see the drug at either 20 mg or 30 mg being really well tolerated, like sub-10% discontinuation, really no idiosyncratic events. A good dose response between 20 mg and 30 mg, which gives us what to go from here and allow us to take a little bit of a step-back right now and ask again what is the drug for. And I think the more we look into this and the distribution of the patients and what they're in, the closer it gets to the original profile of the drug, that it's really a great drug for the 60% or 70% of the patients and that's probably where we should be focusing the development moving forward.

And yes, it's going to be used in the hyper-refractory patients. That's why the study was the highest seizure burden ever in a study, that was this POWER1, which is accomplishing the fact that we got a lot of very severe patients, but also talking about the limitations of getting the severe patients. So a few things to tighten up for the next studies, but we are quite optimistic about how to move forward here.

Great. Well, Marcio, Tim, I didn't even get to elsunersen and the rest of your pipeline. So I apologize for that. But next time. So thank you very much for being here.

Thanks. Appreciate it.

Thank you for having us. Appreciate it.

[Audio Gap] Praxis, who's going to run through a presentation. Megan?

Thank you. Thank you. Good afternoon. I'm Megan Sniecinski, the Chief Operating Officer at Praxis. Building on a remarkable 2025, we've continued executing across our portfolio in our journey to become a commercial company, and we're gaining momentum across all of our 4 late-stage assets.

These are our forward-looking statements. Everything we do at Praxis is -- comes back to one thing, accelerating the delivery of life-altering therapies for patients suffering from CNS disorders, many of whom have been waiting for decades. Looking at our near-term horizon, what's ahead for us this year sets us up well to deliver on this mission.

I want to use our time today to share more about what's happening across each of our programs, what we're excited about and what lies ahead for the company. Our broad pipeline has several near-term catalysts and we're heads down executing to deliver on them. Our ulixa NDA in essential tremor is under review with a PDUFA date late January 2027. And ahead of that, we have our NDA for relutrigine under priority review with a PDUFA date in late September.

At our earnings call last week, we also announced that recruitment was complete for our EMERALD study in broader DEEs with top line results reading out in the fourth quarter of this year. And looking to vormatrigine, we have our POWER1 Phase III study readout this quarter, and we'll be initiating the POWER3 monotherapy study, a milestone this community has been waiting for, using all of the existing exciting features of the vormatrigine profile to deliver on what patients need. And then later in the year, we'll complete the POWER2 Phase III study. Enrollment is progressing well, and we're on track to finalize it later this year and report early next year.

And looking at elsunersen, we recently reported results from our EMBRAVE Part A study. And EMBRAVE3 is now enrolling and expected to complete in 2027, serving as the registrational trial for our NDA filing. We're building towards four first- and best-in-class CNS therapies over the next 2 years, representing more than $20 billion in peak sales potential. Our cash position of $1.4 billion at the end of March positions us well with a runway into 2028. Putting us beyond the launch of relutrigine and ulixa and giving us the resources we need to continue executing and creating value for patients.

Let me start with ulixacaltamide and essential tremor, a disease that's been completely neglected for decades and where we're about to change everything. Essential tremor is one of the most common movement disorders affecting 7 million Americans. And yet there has never been a single FDA-approved therapy specifically for this disease. ET patients struggle to write their name, to eat with a spoon, have a hard time even pouring a glass of water to drink. And these are not minor inconveniences. These are devastating daily losses. And we estimate approximately 2 million patients are seeking treatment and seeking a therapy that can meaningfully improve their daily function. This represents about a $10 billion in peak sales opportunity in the U.S. alone.

Our Essential3 program was comprised of 2 Phase III studies, a placebo-controlled parallel group design and then a randomized withdrawal study design, with a very unique design feature that allowed study allocation and treatment allocation to be fully blinded between participants, study staff and investigators. At AAN last month, the Essential3 program was awarded the abstract of distinction in movement disorders, a very meaningful recognition for a study at the most important Neurology Congress in the U.S. During the plenary presentation, we showed the baseline disability of the trial participants, which mirrors what's seen in clinical practice.

What stands out is that over 90% of participants reported worsening in the last 3 months. And this speaks to the progressive aspect of the disease. And then in the data on the chart you see here, you can see the extent of significant disability across everyday activities that these patients experience. Essential tremor impacts all aspects of functioning. With the unmet need so high, we are thrilled Essential3 is the first successful Phase III program for a drug in essential tremor. Both Phase III studies were positive with clinically significant and statistically significant results across both primary and secondary end points.

And then on safety and tolerability, we saw no drug-related SAEs and the treatment-emergent AEs were mild, occurred early during titration and resolved. And what physicians tell us is that they feel very comfortable managing these side effects in the context of proactive patient counseling.

At AAN last month, we also shared further data supporting the rapid, deep and consistent drug effect we observed across activities of daily living and other outcome measures. Patient reported and clinician-assessed outcomes all move in the same direction. And it's this kind of consistency that really builds physicians' confidence. When we look at the extent of response in our combined analyses, we see remarkable gains in functioning. These results were statistically significant at all responder thresholds and this real robust data represents true functional gains for patients and to have nearly half of the patients regaining 4 points is remarkable. And that's why we're seeing strong interest and engagement from the medical community.

Earlier this year, we conducted a very comprehensive observational study with physicians to understand their view of essential tremor and ulixacaltamide. We surveyed over 2,000 physicians in the U.S. who collectively manage over 40,000 ET patients, and the results were beyond encouraging. They validated ulixa's profile across efficacy, the breadth of benefits as well as the tolerability profile. It's clear ulixa addresses a need physicians have felt for decades. The pent-up demand is real and reinforces the $10 billion peak sales I mentioned earlier and also demonstrates the real need for a drug like ulixa in the market.

We also surveyed almost 1,300 patients, and the activities they told us were impacted most are exactly the activities where Essential3 showed benefit. It's truly exciting to be at a place where there is such alignment between the physicians, the patients and the results of our program. We are full steam ahead on our commercialization and build, we have our leadership in place and the field force hiring is on track for completion well ahead of the launch, where we want to have the field teams in place and trained well in advance of our PDUFA date and we continue to expand and build the commercial infrastructure across all commercial areas.

We've also successfully established a distribution network to ensure drug availability at launch in sufficient levels and we continue to engage with the health care professionals, including launching the ESSENTIAL to me disease state awareness campaign last month at AAN.

Now turning to vormatrigine, our common epilepsy program. Vormatrigine is the most potent and selective sodium channel modulator ever developed in epilepsy. With over 3 million patients affected by this disease, we see 1/3 -- over 1/3 are changing their medications each year and nearly 2/3 have to be on 2 or more antiseizure medications. The patients are simply cycling through treatment options that don't work well enough, and they deserve better. And this represents the differentiation vormatrigine can bring to patients, and it goes well beyond just the efficacy. It's once-daily dosing, no food requirements, fast-acting, no titration, and minimal DDI risk. And these are the features that physicians and patients have been asking for. We know physicians need more good drugs for their patients. And vormatrigine represents that real differentiation, and we're positioning it for broad foundational use in the treatment paradigm.

At AAS in December, we presented the full data from our RADIANT study, where vormatrigine demonstrated best-in-disease potential in focal onset seizures. Vormatrigine has fast-acting efficacy without the need for titration and the effect continues to increase with more treatment time. Additionally, we saw that vormatrigine improved efficacy on top of other common anti-seizure medications that patients were taking.

As I mentioned earlier, there are 3 key milestones in the near future for this program. The first is the readout of POWER1 study this quarter and POWER3 is set to generate data in the context of monotherapy treatment, which the majority of the market really needs. And enrollment is progressing well in our second Phase III study, POWER2 and we're on track to finalize that this year and read out early next.

In our DEE programs, we have 2 complementary assets that together have the potential to address real need in epileptic encephalopathies. Relutrigine stands to become the first approved therapy specifically for SCN2A and SCN8A-DEEs, severe childhood epilepsies, where seizures can begin in the first weeks of life and where nothing works for these children. Our clinical profile is ideal. It's once daily, no titration is needed and a pediatric-friendly formulation that can be given orally and it's designed for families caring for severely ill pediatric patients. The EMBOLD study was stopped early at interim, where we delivered overwhelming efficacy. And we saw relutrigine treatment leading to a clinically meaningful and statistically significant change in seizure frequency and associated developmental endpoints, like disruptive behavior, alertness and communication.

Beyond these impressive results, the effect of relutrigine was rapid, durable and continued to deepen with time and the strong efficacy results and a favorable safety profile really underscore relutrigine's best-in-class potential. Looking at DEEs broadly, you simply cannot have seizure activity without participation of the sodium channels. Across all DEEs regardless of the underlying genetic etiology, hyperactive sodium channels are in the pathway and relutrigine addresses that common mechanism. The current U.S. DEE market is over 200,000 patients, approximately 20x the initial 2A and 8A population. If EMERALD is positive, this becomes one of the largest rare disease commercial opportunities we know of.

We shared last week that recruitment of EMERALD is complete in record time. And it's clear caregivers, patients and investigators share our view of the potential of relutrigine. Our top line readout for EMERALD will be in the fourth quarter of this year. We build the foundation with the potential launch of 2A and 8A and the results of EMERALD later this year, if positive, will significantly expand the commercial potential for relutrigine by several-fold.

Lastly, let's talk about elsunersen, the first ASO in our platform. We recently presented exciting results from our Part A study, and we're thrilled with the impressive seizure reduction as well as disease-modifying components that we saw. The overall data from the EMBRAVE program and open-label extension as well as our emergency access program really set up the potential for this to be a transformational drug in DEEs.

So in conclusion, we are off to a great start with momentum across all of our clinical profiles -- programs. We're on track for our commercial launches in both relutrigine and ulixa and we're backed by a strong balance sheet and a broad IP portfolio across our programs, we continue to be focused on our execution and delivering innovative therapies for CNS. Thank you.

Good day, ladies and gentlemen, and thank you for standing by. Welcome to the Praxis Precision Medicines First Quarter 2026 Financial Results Conference Call.

[Operator Instructions]

As a reminder, this conference call is being recorded. At this time, I would like to turn the conference over to Mr. Dan Ferry of LifeSci Advisors. Sir, please begin.

Good morning, and welcome to Praxis Precision Medicines First Quarter 2026 Financial Results and Business Update Conference Call.

This call is being webcast live and can be accessed on the Investors section of Praxis' website @www.praxismedicines.com. Please note 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, they 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 on an obligation to do so. Please refer to Praxis's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis, and Tim Kelly, Chief Financial Officer.

After providing updates on our key programs, we'll move to a brief Q&A session where Marcio and Tim will be joined by Steve Petrou, President of Research and Development, and Megan Sniecinski, Chief Operating Officer.

With that, it's my pleasure to turn the call over to Marcio.

Thank you, Dan, and good morning, everyone, and thanks for joining Praxis' First Quarter 2026 Conference Call.

Building on a remarkable 2025, we have continued executing across our portfolio in our journey to become a commercial company with strong momentum building across 4 late-stage assets, representing more than $20 billion in peak sales potential.

With the NDAs for ulixacaltamide and relutrigine accepted by the FDA and PDUFA date set, we're ramping up commercial efforts to support the 2 potential U.S. launches within the next 8 months while also making significant progress with our other clinical programs.

It's also incredibly exciting to announce that we have completed recruitment for the EMBOLD study in the broad DEE population, with top-line results expected in the fourth quarter of this year, which we expect to support a potential supplemental NDA next year.

We're also on track to report results from our POWER1 study for lamotrigine later this quarter.

Also made exciting progress with our solids ASO platform with the positive results from the EMBRAVE Part A showing a disease-modifying effect of easinersen in SCN2A early onset DEE and substantial reduction in monthly seizures, amongst many other results.

With key hires made in our commercial organization and a strong financial foundation, we're accelerating the delivery of life-altering treatments to patients with CNS disorders.

Let me provide a bit more detail on each one of our programs. Let's start with Ulixa. FDA acceptance for Ulixa's NDA marks a meaningful step forward for the 7 million Americans living with essential tremor who currently have no ET-specifically developed treatments approved.

We estimate that about 2 million of those people living with ET are in immediate need of a therapy that can clinically improve their daily lives, representing a potential for over $10 billion in peak sales.

To unlock the benefit for patients and the value, we have been diligently preparing for our commercial launch based on the PDUFA date of January 29 next year.

The commercial leadership team is in place with our field force plan to be hired and trained in advance of the launch, and we continue to expand and build the commercial infrastructure across multiple areas, like operations, marketing, access, and compliance.

We have also successfully established a distribution network to ensure drug availability at launch at successful levels.

Earlier this year, we conducted a very comprehensive observational study with physicians to understand their view of ET and ulixacaltamide. We surveyed more than 2,300 U.S. physicians who collectively manage tens of thousands of patients.

The results were beyond encouraging. They validated the ulixacaltamide profile across efficacy, the breadth of benefits, and tolerability, reinforcing the more than $10 billion peak sales potential and the need for a drug like Ulixa in the market.

Importantly, we also wanted to hear more details from patients and conduct a similar work with over 1,300 ET patients, which further validated the agreement between the needs of patients in terms of their functional benefits and the results of the Essential3 program.

It's truly exciting to be in a place of such alignment amongst treating physicians, patients, and the results of our program. We're also very pleased with our robust presence at the American Academy of Neurology Annual Meeting last month.

With 15 scientific presentations, including a plenary presentation highlighting the Essential3 program results, which received the AAN's abstract of Distinction and Movement Disorder Awards, which underscore the strong interest and engagement of the medical community.

To further enhance our engagement with health care professionals, we have launched the Essential2 Me disease state campaign. Let's now move to our epilepsy programs.

As we shared in March, in another pivotal moment for practice and patients, the FDA has accepted with priority review the NDA for relutrigine for seizures associated with SCN2A &8A-DEE.

Those are severe patients affected early in life, and where the seizures are intractable from the very beginning.

It's important to highlight that if approved, relutrigine would be eligible for a pediatric review voucher.

With the PDUFA date of September 27, preparation for launch is moving full steam ahead with continued hiring of commercial roles, building sufficient inventory, establishing a comprehensive patient support program, and engaging with payers to ensure timely access upon potential approval.

We remain confident in the clinical potential for relutrigine and the benefits to the broader DEE population. With recruitment in the EMBOLD study now completed in record time, it's clear that patients and investigators share our view.

The potential launch in SCN2A &8A will build the foundation and the results of the EMBOLD later this year; if positive, it will significantly expand the commercial potential for relutrigine by several folds, considering the broad DEE population is comprised of over 200,000 patients in the United States.

Let's now talk about vormatrigine, the most potent and selective sodium channel modulator ever developed for the 3.5 million people living with epilepsy in the United States. We have 3 key milestones in the near future for the program.

The first is the readout of the 401 Phase III study later this quarter. Then the initiation of the POWER3 study, a milestone in the community, using all the exciting features of vormatrigine to deliver on what the majority of the market really needs.

And then later in the year, the completion of the POWER2 Phase III study, which is evaluating doses of 20, 30, and 40 milligrams once daily. Enrollment is progressing well, and we're on track to finalize the study this year and report early next year.

Lastly, let's talk about Elsunersen, the first ASO on our platform. also has a rare pediatric drug designation and is being developed for the treatment of early seizure onset patients with SCN2A mutations.

We have recently reported the results of EMBRAVE Part A, which enrolled 9 children aged 2 to 12 who were randomized 3:1 to elsunersen or sham over 24 weeks.

We are thrilled with the impressive 77% placebo-adjusted reduction in monthly seizures and the disease-modifying components seen across multiple domains in those patients, while maintaining the generally safe and well-tolerated profile.

The overall data from both the EMBRAVE program, open-label extension, and emergency use program globally highlight durable seizure reduction and meaningful global gains, which further underscore the transformational potential of this drug.

In conclusion, we're off to a great start with our momentum continuing to accelerate across our clinical portfolio, preparations for the commercial launch of ulixacaltamide and lamotrigine well underway, the completion of the EMERALD study enrollment, POWER1 top-line readout coming up, and many other achievements to come.

Backed by a strong balance sheet and a long, multilayer IP portfolio across the programs, we're focused on rigorous execution and driving progress across our innovative first and best-in-class portfolio of CNS therapies.

I'll now hand over the call to our CFO, Tim Kelly. Tim?

Thank you, Marcio. Good morning, everybody, and thank you for joining today's call. I'll provide a quick summary of our first quarter financials.

In Q1, our operating expenses were approximately $106 million, with $78 million of that for R&D and the remaining $28 million for SG&A, driven by ramping activities and hiring related to commercial launch preparations.

During the first quarter, Praxis spent $86 million in operating cash compared to $53 million in the first quarter of 2025, reflecting greater clinical trial activity, headcount growth, and commercial launch preparations.

As of March 31, 2026, Praxis had $1.4 billion in cash, cash equivalents, and marketable securities compared to $926 million as of December 31, 2025.

This increase of approximately $474 million was primarily attributable to net proceeds from Praxis's January 2026 follow-on public offering and interest income on marketable securities, partially offset by the previously mentioned cash used in operations.

The company's cash, cash equivalents, and marketable securities as of March 31, 2026, are expected to fund operations into 2028. With that, I will hand the call back to Marcio.

Thank you, Tim. I appreciate the review. We're going to move now to Q&A. Howard, maybe you can provide the queue for us.

[Operator Instructions]

Our first question or comment comes from the line of Yasmeen Rahimi from Piper Sandler.

Maybe also congrats on EMBOLD bringing to the finish line enrollment and data in 4Q as it's an important readout this year.

Maybe remind us, what is the data that we have to support relutrigine working in a broader DEE population, both across preclinical and clinical data?

And then also, what do you see on a blinded basis across safety and efficacy that continues to give you confidence in the high success in the EMBOLD study? And I'll jump back in the queue.

Thanks, Yas. I'll take a step back here and maybe talk a little bit about the genesis of going to the broad DE population.

When you look into seizure activities, particularly on those intractable conditions like DEEs, we know full well just how difficult those patients are to control.

I know that when they can have at least some partial control for the most part, it is because that is a way to inhibit the block, better modulate their sodium channel activity, like you simply cannot have seizure activity without participation of those channels.

So when we were conducting the EMBOLD program for SCN8A, the #1 question we're getting from physicians back then was, " When are you going to expand this to this [Indiscernible]?

So we'll take that into mind in terms of the overall clinical proof of concept, payer idea, and the needs that we're seeing. But we had to slow down a little bit and do a lot of work.

And you might have seen, and it's available on our website, a fair bit of the work in terms of different animal models, which are incredibly predictive in epilepsy, on understanding whether or not there was a good scientific rationale on top of the electrophysiology rationale, on top of the molecular rationale to go to this.

Then, in the last part, we had to make sure that the FDA was in agreement that we could study in this population. Safety is paramount, making sure that we're actually understanding the populations we're in.

So when we checked all those boxes, we're able to initiate the study. I think what is incredible, I would say, is just the level of interest.

If you look into ourselves, if you look into other studies indeed before, if you look into competitive, and I'm going to put that very loosely, there were studies that are going right now, there was no interest in those others.

It's pretty obvious by the pace of enrollment that is happening with us and with others out there. And the #1 reason why is that physicians are very confident in the Ada here, just like we are.

So it gave us, of course, this extra ability to move things forward. But if I can turn to the business for a second, we are in the business of helping patients. But at the same time, the only way to continue to help them is to continue to generate proper positive returns to invest in the future.

The expansion towards the DEE is like 20-fold what the initial indication for SCN2&8A is, which is incredibly important. But the second part makes not only scientific sense, but it's a tremendous upside in terms of the potential of this drug.

Then lastly, I know we keep piling catalysts throughout the year, and you guys might be tired of us having so many readouts. But we thought it was very important to get that, shortly thereafter, to really, with a fresh, hopefully, approval at that point in time, give the FDA a lot of flexibility to actually look into just the additional data and potentially even qualify for certain accelerated mechanisms that have been available.

So all in all, we see this as a tremendous and maybe the key updates today that we're giving in terms of value inflection for investors.

Our next question or comment comes from the line of Ritu Baral from TD Cowen.

A lot of client questions are just around the upcoming power readout and what our expectations should be.

Knowing the baseline and knowing the relative baseline of other competitive therapies, how should investors, how should we be looking at placebo-adjusted seizure reduction, the safety profile?

And then how might that data then frame the Power2 and 3 studies, given the different doses in those studies and the different dosing paradigms?

Great set of questions there, Ritu. So, I think let's start with the baseline, that's what you mentioned.

So if you look historically, at least in recent history, baseline for focal seizures in the refractory population, so 1 to 3 ASMs, and you know the drill there on the other criteria, have been hovering around like 9 to 11, 12 countable seizures on the previous 28 days.

And I think we're probably a little higher than that, a tiny bit here for POWER1, which was what we're aiming for. We knew these patients were fairly refractory or very confident about the drug.

We also wanted to make sure that once we establish there and have very clear efficacy as we expect, allow us to move incredibly quickly as well towards the ultimate goal of this drug that's being widely available for any patients with focal seizures and in the future, other types of seizures as well.

That brings us to the second part of your question, which is the expectations. And I think that it's always dangerous to talk about expectations and setting bars, artificial bars, this late in the game, in terms of like literally like weeks, I would say, before readouts.

But we've been fairly consistent on the expectation here throughout the years is, number one, as the severity increases, I think this is one of the few areas, and we're going to be very excited about science that the new drugs still deliver a lot.

We just saw that recently with another program; we expect to see the same, like here, a drug delivered despite being piled up with a lot of other drugs. It is at a higher baseline, so more severity.

And we've historically been giving that adjusted by placebo around 30% or so as quite meaningful because when we talk to physicians, when you look into the active prescription pattern, that seems to be a number that lands incredibly well.

And then the last part is safety, as you mentioned. And we're very confident about the safety profile of this drug, both what we're seeing in the blinded, based on POWER1, or also what we are seeing on a blinded basis, POWER2, which was the very last topic you mentioned.

So fairly comprehensively, I think we're excited about the upcoming readouts, another card to flip, another program to hopefully accelerate to bring to patients.

POWER2 is going really well. So, as you saw as well in the press release, we reiterated finalizing the study by the end of the year and reading out early next year.

So all in all, to think about a potential third or fourth drug or a potential third submission of an NDA or account for this NDA in 12 months is no joke, and we are very, very proud of that.

Given that baseline, what about seizure-free, Marcio? Last question, I promise.

No, no, like Nick one there. I think, again, we should unblind it. I do feel the #1 thing is really to make sure we have a very solid reduction.

But of course, we want to see seizure freedom here as well. It's important. It's something we saw on the RADIANT data, that when you treat patients longer, by week 10, 12, your median seizure gets to 100 percent reduction.

So of course, we want to see the more we treat, the longer we treat patients, a very deepening of effect, that's what started seeing. And I'll leave like that, but we're excited with the overall profile.

Our next question or comment comes from the line of Tiago Fauth from Raymond James.

I had just one quick one on Ulixa. It's also related to the communication plan for the Street on the regulatory interactions still a huge area of focus with investors.

So I'm curious what's the level of detail that the Street can expect around mid-cycle review, labeling discussions, CMC inspection scheduling, or anything related to that?

Thanks, Tiago. So maybe, again, I'll take another step back here as well. So we are, of course, being communicated by the FDA when the expected mid-cycle meetings are going to happen for both programs, their communication pattern with us, when label negotiation is expected to start and be completed, and the entire cycle.

So we have very good visibility from the agency's goals and from the conversations with us in relation to that. I can tell you that throughout this process, I think a very good shift, I would say, on the FDA is just the ability to really try to keep communicating with the companies throughout the process, and we are seeing that in both programs, which gives us -- I'm going to be cautiously optimistic here about a good level of comfort on how the process is moving on both drugs.

Having said that, I think it would not be appropriate for us to give play-by-play. And at the mid-cycle, I think the expectation on our end is that they're going to be like no major concerns, keep reviewing, keep like finalizing, crossing the Ts and dotting the Is.

And if that's the case, I think we should expect very little from ourselves. Of course, if something meaningful happens on those meetings, either on the view of like maybe they want to see something or the opposite.

They are moving faster, and maybe they want to accelerate things. I think it would be appropriate for us to have a discussion. But we need to get to that point with both publications to be able to have a discussion.

I know you asked Ulixa, but I want to make sure our equally lost child gets some attention here with relutrigine.

Our next question or comment comes from the line of Francois Briesbo from LifeSci Capital.

Congrats on the EMBOLD recruitment there. I was just wondering, maybe if you can help us understand, obviously, the patient population size is quite different between IIa and 8A, and then going to broader.

But I was just wondering on the broad side, how different are these patients? And my question is geared towards expectations. Is it that the IIa and 8A are so severe that if we look at that data, that kind of sets these artificial bars or whatnot on expectations for the broad DEEs?

Or is that a dangerous game based on maybe the heterogeneity of the patients? Just a little more understanding of who you are going after with these broad DEEs?

Yes. And thanks. I'll split that question into 2 parts. So, one, it is kind of insane to think this way, but it is the reality of the market.

When you go to these patients and to the physicians, and we understand their clinical course and just how the disease is a downward slope, it only gets worse over time for those patients, unfortunately, leading to all sorts of complications and SEP and so on.

It is very clear that improvement, any improvement, would be the bar, meaning stat sig is the bar for the ERL study. Of course, we want to deliver the best possible results for those patients, but I also think we have to be very careful about setting up the bar.

And as I said, in relation to the previous study with POWER1 on Ritu's question. So here we are in a situation that is a very large market, but that is nothing. It's the end of the line.

If you think about the patients, then over time, we expect to give them a lot. But I think for this study, we need to be happy if we see statistical significance as we expect to and some improvements.

Now, to go to the other side of the question, how heterogeneous is this population? Our recruitment strategy was very clear as to what we want these patients to be diagnosed with.

So that's very serious, has to be early, has to have a developmental impact together with seizure onset and a number of countable seizures at baseline.

Having said that, we want the most diverse group of patients possible because that's what we're going after. That's what no other drug can do right now. And we accomplished that.

By definition, one could argue that IIA and A are harder to treat, but this is more heterogeneous to treat. So if you can see even half, I would say, what we're seeing on EMBOLD would be just doing -- it's even hard to imagine how big a market that would be.

But if we see just stabilization and improvement in these patients, that would be incredibly meaningful. So, on setting it up, what is meant to be a really major opportunity for all of us.

And maybe if I could sneak in on AAN, obviously, I think the plenary was passed, like about 8,000 people attending. And so can you just talk about your interactions with neurologists and movement disorder specialists, does that trigger any interest for ex U.S.?

Can you share what you guys are thinking on the ex-U.S. stage for [indiscernible]

Yes. Thanks for reminding us of something that I think we get so excited and so wanting to move forward as always, that sometimes we only stop, slow down, and smell the roses.

Yes, being on that plenary at AAN in Chicago a couple of weeks back, and with about 8,000 physicians attending, being the first one to recognize the most important clinical study presented at the meeting.

It was very emotional for some of us, for me, certainly. But the cort the most cort was actually the number of people who came afterwards to us and wanted us to go to their practice with our medical affairs team and present to the entire practice and orordentist start thinking and so on.

So it just reinforced now there's a huge interest in ex-U.S. as you can imagine, we believe and to be very clear, this is, first and foremost, a U.S. opportunity right now.

We're putting our heads down, and we're executing the U.S. There are multiple implications of current policies in the United States, particularly the pricing policies that I would say don't excite us too much to explore split strategies outside of the U.S. We wouldn't put at risk the U.S. business.

So this is something that someone has to do globally. And of course, we're planning to eventually get there. But we're not really too excited about splitting the geographies with anyone else.

Our next question or comment comes from the line of Yatin Suneja from Guggenheim.

Congrats. A very nice update. Maybe 2 questions for me. Marcio, you addressed the expectations for POWER1.

So the follow-up question I have there is that at least in POWER1, we're going to get data on the 30-milligram QD dose. So could you maybe talk about the potential to capture additional efficacy with the 40-milligram in POWER2?

Just love to hear from you, how should we think about the 30 and the 40 if there is any potential there?

And then a broader question on the commercial side. I mean, obviously, you are undertaking 2 big launches in the next, let's say, 6 months or so. So could you talk about the manufacturing, supply chain, all of that stuff, where do you stand there?

No, of course, yes, maybe even starting with that. So we imagine when we are planning these launches, we're like, okay, what is likely to happen? And that's how we set our base and how we set the financial expectations, and you see in our forward-looking statements, and overall, you are saying that.

And then we go, and we talk to the market, and we start to be maybe a little conservative on some of those. And what if we're wrong on the upper side of that? And then what if we are wrong by several folds on the upper side of that? And that's how we have to plan supply in our view.

And that's what we've been doing. We're glad for Ulixa, for example, to have dual like 2 completely independent drug substance manufacturers. They are being rock and rolled for us to have inventory.

We're talking about metric tons of drugs here, of Ulixa, just to give you an idea of scale. This is not like a small scale in general, but a very large scale. And we're also quite happy with the fact that the process is relatively, I'm going to say, in the grand scheme of things, simple, and we've been able to align that with the FDA before the submission.

So we're good there. Relutrigine, of course, the scale is smaller for 288, but it's not small for GE. So we're thinking about that as well, and we're preparing for that for the launch, too.

Very different distribution strategies, as you can imagine, a much more full white glove-like one-on-one interactions all the way to the point of use with the relutrigine, and we are building like that. And then on the Ulixa, we want to do a one-to-one as well.

But of course, there's a little bit less downstream here.

So both the inventory and management of the patient taking the drug have been quite sorted out. If I go back to your POWER1, POWER2 interrelatedness question, 20, 30 milligrams of POWER1, we believe we're going to see very, very strong results there.

But that begs the question: Is there even more to come? So if you look into recent history, very, very recent history, what we're seeing is companies dabbling with the issue of even a little bit more drug, and you trip the wire, and then the drug becomes completely useless from a clinical practice perspective.

We saw that in our results a few weeks back, when there are 2 dose and the top dose cannot be used at all by patients despite delivering a little bit more efficacy on paper.

But that is not the case here. We know that that is not a limitation with Uoraserene. So when you think about the need of patients and the 3.5 million, not the 30,000 that maybe others are going after, that is the real market we're going after, and it requires understanding the heterogeneity of all those patients.

That's why having the ability to deliver meaningful either 20, 30, or 40, you name it, is so important. So as not to create expectations that it could be even better.

But of course, by definition, it could be even better there on POWER 2. So we'll get there soon, and we're going to be able to review it. I hope I answered your questions.

Our next question or comment comes from the line of Kambiz Yazdi from BTIG.

Three for me. On Ulixa, with the Essential to Me disease education campaign launched in April, can you give us a sense for the early response from health care providers and how you think this initiative is going to translate into the top of the patient funnel heading into the PDUFA, maybe briefly on relutrigine.

I know you touched base on Mario, but how were you able to enroll EMBOLD so rapidly compared to competitors in the DEE space? And lastly, on vormatrigine, you commented a little bit about blinded POWER1, POWER2 safety.

How are you handling the investigator's option to reduce the dose of background medication in POWER1 relative to the RADIANT study?

Sounds good. I'll try to tackle all of them so I can move on. So Essential to me was something we developed with patients and the way they see themselves.

And I think once the reaction from the providers is fantastic. Like, people really love it. They see their patients. It reminds them to act, and so we're very happy with this.

It will, and it's already doing a great job on building further our database prelaunch to understand really who would be the first in line here, both on the providers and on the patient. We're going to give more of an update next quarter as well.

How did we enroll EMBOLD? I would say to go back in time, and people would ask, and maybe I'm going to be criticized by the comments, but I'm going to give it a try.

We would ask Jordan how it could be Jordan. They would go back to the court, and would train and would understand the shots that worked and the ones that didn't. And it wouldn't take any wins as a win, but as an opportunity for the next win to work.

I think we're never going to be as good as Jordan was, but I think we're pretty serious about every single day asking ourselves, how can we do better, because these patients need us.

We're pretty good as well on actually getting sites that have a large number of patients and therefore, have the ability to enroll, and they understand us from the beginning, meaning they understand that our expectation is the highest quality, first and foremost.

But also high speeds in terms of you don't sit on queries. We don't sit on the eligibility form. You don't sit on a meeting that's going to happen next week. You need us, we're there immediately. And I think our team is, if I were to say fantastic, they will be fantastic at doing all of this because everyone is here for one single reason is to help these patients.

So that's as simple as that. And I think there was a last question that I actually forgot now.

Yes. Just briefly, on vormatrigine, you talked a little bit about blinded POWER1, POWER2 tolerability.

How are you handling the investigator option to reduce dose and background in POWER1 relative to what was observed in RADIANT?

Yes, absolutely. So what we learned from RADIANT, we've got both pragmatic and programmatic reduction systems in POWER1.

One must be very confident in what the investigational drug does to allow for the background to be reduced. Others reduce the investigational drug, as you know, because they don't trust the drug so much, not in our case.

So we allow that to happen. I will tell you, it happens partially, which is obviously very important. But I think it was very effective as well.

It's the same algorithm for POWER2. I think physicians are very happy with how it's done. It's very safely done, although very logical, the way it's done, considering the fact that the background, sometimes on a placebo, creates circumstances as well, which is required.

So it keeps the blinds, keeps the integrity, but at the same time, manages the study in general. So super happy with that as well.

Our next question or comment comes from the line of Ami Fadia from Needham & Company.

This is [indiscernible] on for Ami. For focal onset epilepsy, are there any first-to-market dynamics you see if Xenon's product is first to market?

Our KOL checks have been overwhelmingly positive for vomacigine, but I just wanted to understand if there are any other factors that may have an impact here? And also, have you had any early discussions with payers on what data you need to generate to support earlier line use?

Yes. So I think when you look into the overall market, and we did a lot of work on this, it's very sad in a sense that when you go outside of the very small number of patients that are treated at Level 4 epilepsy centers, and you go to a much larger market outside of that, these patients are failing at very high proportions.

They are like switching medications, like they're adding on top of that, and so on. So I said this before, I don't believe that it is a one-winner game here that if we had 10 other drugs for focal seizures, that would be needed.

What we have right now is completely inadequate. Having said that, the biggest complication throughout the years is when you get a drug, and you really can't allow the physician to have the flexibility to tailor for their patients' needs.

And I think what we're seeing with vormatrigine is that it gives a lot of flexibility in terms of what can be done, as we just discussed on the previous question, for example, and it's not the case for other potential competitors here.

But also pretty confident about our overall pace. Being a few months behind, and reminding all of you, we were way more than several months behind the other DEE study not that long ago, and now we're reading out soon, and the other study is not even reading out until late next year.

So I'm not sure if a few months is really a first-mover advantage. And I don't believe there was ever a mechanistic sodium channel modulator removed from the market, but there certainly was for the other mechanism that you mentioned, and all the safe signals are showing up there as well.

So, I think the physicians we talk to are happy about having more options, but cautious about things that they've seen before not happening too well or working so well for patients on the safety side.

So we'll play that. We'll play our press on the market, and I have no doubt we're going to win.

Our next question or comment comes from the line of Andrew Tsai from Jefferies.

Appreciate all the updates. I know we've talked a lot about the EMBOLD study. I did have one small pointed question about it.

When you guys shared the IIaA data, 53% placebo-adjusted reduction overall, curious if you saw a consistent seizure reduction in both or each of the 2 DEE subgroups.

Maybe that can give investors confidence that you'll see robust and consistent efficacy across the broader DEE subgroup. So, would it be possible to share the seizure reduction in both subgroups?

And then for ET, I appreciate all the AAN analyses and so forth. And maybe based on your ongoing work on a friendlier titration schedule, ultimately, should this be approved, what kind of compliance rate do you expect to see in the real world?

How long do you think Ulixa responders could be on the drug for?

Thanks, Andrew. Maybe I'll start with ET, and then we can move back to IIA on EOL and in general.

So when you ask physicians, and we had a number of advisory boards and this insanely large overall observational study, we asked them how they would manage and what the expectation is.

I think the positive surprise for us was just like how comfortable they were in managing what we know to be a tolerability concern that happens on the first few days and first few weeks of this drug.

We're going into this launch fully aware of that being the single most important driver of retention of patients in the long run, and they're incredibly comfortable, and we're actually telling them the things that we thought they could do in terms of like calling these patients and then advising them better, and so on and so forth. So very comfortable with that.

Now, how does that translate to overall retention over time and financials?

There are 2 approaches here that we can take. One is saying what the things we're thinking about, and that is your classical oral chronic therapy compliance and retention.

So starts anywhere from the 60s to 80%. That's just overall numbers out there. And then what is the minimum to sustain the forecast we put in front of you all to be over $10 billion?

That number is way smaller. So I'm not saying the number will be smaller. I'm saying I'm going to have to believe in something to go into a forecast, and we don't need to believe a lot to go to $10 billion plus. And that gives us insane comfort.

We also have hundreds, hundreds of patients in the safety database, as you know, that have been on this drug for 6 months, 1 year, 2 years. So that gives us a very good indicator of how persistent all these patients are.

The second question is actually very appropriate to be asked right now, the results on 2A and 8A, despite the fact that the manifestations, the electrophysiology, and the overall clinical manifestation of NaV1.2 deregulations and NaV 1.6 deregulations are very different.

The results are quite similar and very good in terms of the overall reduction, developmental gains, and seizure freedom. So it gives us insane comfort that it is so similar across 2A and has all very good points. Thanks for reminding us to make the highlights.

Our next question or comment comes from the line of David Hoang from Deutsche Bank.

So I just had a couple here. Maybe back to vormatrigine in focal epilepsy across POWER1 and POWER2, I know you're looking at 3 doses, 20, 30, 40 mg. How many of those doses would you like to actually take to market?

And what do you think would be the best number for commercial viability? And then in terms of the POWER 3 study, the monotherapy study that you also intend to conduct, could you talk a little bit about how that fits into your broader plans for vormatrigine? And why aren't other sponsors pursuing monotherapy studies like that?

Thanks so much for the question, Dave. So 20, 30, 40, when you started S20 for POWER1, and the part is like normally, people start, if you go to the public documents for like other sponsors, for example, everyone is going to be like, " How close to the MESCC50 can I get when you translate that to humans?

And I'm going to be pretty close to that because I can go much higher. We can go much higher here. So we're like, where we started the drug is going to be clearly effective.

So that's where we started. And where do we end for now, when we believe that's kind of the maximum efficacy? And I think that's the bull that we are seeing.

But a pretty big feedback from the thousands of neurologists that treat this patient is that flexibility is important for them as they're going through different patient types and different comorbid conditions.

And so we intend to bring all of those to the market because we believe that gives the highest flexibility to physicians and our largest ability to obtain and keep market share.

Now, POWER 3 is a different animal. POWER 3 requires the profile of vormatrigine. So the answer to your question is that others are not doing it because they cannot. Because you need to be able to use this drug as monotherapy.

Now there are steps towards monotherapy. It's not an immediate reduction to monotherapy. It has to be done pretty safely, pretty thoughtfully.

But patients fail because they can't be on one mechanism. The only mechanism that can, if tolerated, as we believe here, vormatrigine can truly stop any seizures is by acting on the IS and by modulating these channels. And we're the only ones that do that right now.

Everything else is upstream of that mechanism. So that's why the confidence when you have a drug like vormatrigine, as I said in my prepared remarks, this is the most potent and most selective ever developed.

So we have this data publicly available for anyone to scrutinize. So that is the confidence there. What it does is to move from what has been in a little bit of the definition of insanity on how these drugs are developed to get more and more severe patients, smaller pools of patients, and they no longer represent the broader market in those refractory studies.

And you're never really addressing the true market, the true unmet needs that are those patients who are struggling to go back to work, struggling to stay driving, struggling to concentrate.

A significant number of patients with epilepsy experience disabilities. They cost themselves, the health care system, and the social security system an insane amount of resources because the drugs they were putting are compounding the issue with the condition. And I think we have an obligation as a company with such a potent, interesting drug to go there and change and revolutionize, as we say, the treatment of epilepsy.

That is the long answer to the question.

Our next question or comment comes from the line of Olson Jay from OpCo.

Congrats on all the progress. This is Cheng on the line for Jay. Maybe a couple of us. First, on the Ulixa commercialization.

Just curious about the feedback from A and the market research you conducted, what do you view as the most important driver of adoption?

And then I think at the end, you also presented some data on the cerium channel modulator in pain. So I'm just also curious about your latest thinking around this opportunity and if there's anything we should expect in the near term?

Yes, yes, of course. Thanks, Jay. So the most important thing for physicians, when we rank -- and as I mentioned before, and I appreciate you bringing up the question, was very extensive testing and really understanding the details from them.

And there are a number of things they really like. They really like the fact that they have never had something targeted for essential tremor. So, having something that the most fundamental mechanism is C-type calcium modulation, and now they have something for that, or soon they're going to have something for that.

The second was actually a little bit surprising to all of us. They absolutely lost the fact that in 2 weeks, for the majority of the patients, you have the ability to have a conversation with the patients and they really have an effect.

They just don't have that right now in a sustainable manner. They like the fact that we tested the durability of the effect in Study 2. And I would say all those things together, and there are many others, really are going to be key drivers of adoption.

And as I mentioned on one of the previous calls about like inventory and building, if anything, they're giving us indications they're going to prescribe to more patients than we originally thought they would. And then the second part of your question about our pain program.

Well, I think we've been, as you can imagine, we're a CNS company. We need to look into areas of science that make sense for us based on our technology, on the one hand.

On the other hand, we do have a fair bit of things that are moving forward as we discussed today, and many more catalysts to come. So we've been taking a measured approach in terms of exploring a number of other areas in science where our molecules and our platforms can play a significant role.

And at AAN, we did present some of the work we've been doing in pain. And you will hear more from us in the future about how we are advancing quite significantly in that regard as well.

Our next question or comment comes from the line of Douglas Tsao from H.C. Wainwright.

Marcio, just starting with EMBOLD, I'm just curious, congrats on completion of enrollment. Obviously, demand was very strong. I'm just curious if you have insight into the subsets of patients that you received?

And were there any particular ones where you saw very strong demand to reflect sort of the magnitude of unmet need, because obviously, for so many of these, there's no approved therapy, and physicians are just basically trying to figure out as they go along, using sort of off-label ASMs.

Yes. Doug, I'm going to be honest, when we went to the sites, and we talked to physicians who presented the protocol. Maybe what I haven't said in the call so far is that we disappointed a lot of physicians by telling them, no, no, no, you've got to stop. You can't enroll more patients in this study.

We really got there pretty fast, and it seems like we have a deep understanding of this, exactly what you just said. There are so many patients out there that there is very little or nothing they can do, even patients who have other drugs technically approved, but they have failed already, or they try to have a suboptimal response.

So it is very broad. Both the phenotype and genotype of patients we got here. And it is within what we expected. And unfortunately, maybe this is a coup in apology, we couldn't get all the patients that wanted to be on this study.

But I think our promise is if the drug works, we're going to get this drug to them in the near future. So really, really happy with everything and all the dynamics here.

And if I can, on a follow-up in terms of vormatrigine. With POWER1, I'm just curious, do you have any insight in terms of the discontinuation rate so far?

Because obviously, I think in RADIANT, there were some discontinuations, but we certainly heard from clinicians that they had patients who maybe dropped out, who they would have provided some additional counseling, just given the robustness ultimately of the drug, they would maybe encourage them to stay in.

Additionally, given the fact that you titrate up in POWER1, if we're seeing any evidence that that is having an effect?

Yes, absolutely. So we're pretty happy with how we got reduced, I would say, the overall discontinuation here in terms of the historical with the program.

I think some of the points you mentioned, people get more experience with the studies, and so on, they get more comfortable managing. So I'll say I think we're very comfortable with that.

I think we're very comfortable with the new benchmark as well, when you consider that drugs people are excited about have like 22% to 25% discontinuation with a further 25% dose reduction on the top dose. That's definitely not what we are seeing.

So we think we are very, very competitive here, considering recent competitive events.

Our next question or comment comes from the line of Danielle Brill from Truist Securities.

Tyler here for Danielle. My question is regarding the total addressable market in essential tremor. So up to 7 million patients have essential tremor, but you recently said that there are approximately 1 million actively seeking treatment.

So what's this gap between the predicted prevalent population and those seeking treatment? And with that, is education still needed in the field for more accurate diagnosis?

And do higher volume academic centers typically have a more accurate diagnosis?

Yes. So there's about like 2 million to 2.5 million patients right now, either who are being treated and seeing a physician at this moment or just done it and are sitting on the sidelines.

So when you go from 7 to, let's say, 2 to 3, it is a drop that is not unheard of. I'll say there are many, many reasons here. It is not a misdiagnosed problem, and I want to clarify that.

This is mostly something they know and they're either not speaking publicly or disclosing or discussing because they know there's a stigma, there's effect I think we just saw this week, Senator Collins speaking about her diagnose of essential tremor in the sense of people attacking that she might not be fit, which obviously is absurd, because this is a progressive disease only of movement, for example, but people are afraid of talking about things like that.

It is a disease that, for the most part, runs in the family. So people are aware. It is a combination of 2 factors. One is the progress. It's how quickly and how far in the disease patients are.

We call that the level of feasibility, and that's what gives us about $3 million. And the other is society, sometimes not being too ready for someone to raise their hand and say they have a condition.

I think the last one is one where you have 2 or 3 family members, and a physician tells the first one, " There's nothing I can do right now because there are no good alternatives available. You did engage the other family members with ulixacalamide coming to the market; hopefully, soon those dynamics will change.

So we bring this to the forefront. One of the reasons why our campaign is called Essential to Me because it's really what is essential for the patients' death.

That's what we want to awaken to that.

Our next question or comment comes from the line of Brian Skorney from Baird.

You alluded to the opportunity to develop Ulixa and the oral T-type calcium channel antagonist in indications beyond ET.

Obviously, you're pretty full with NDA reviews and running another few pivotal studies. So maybe it's a little bit in the background. But just wondering if you had any updated thoughts on the exploration of other indications where Ulixa could have an impact?

And if there's any time frame you can provide, where we might hear an update on that.

Yes. Brian, we selected 2 other indications we're going to be going through. We're just going through the last, I would say, checking everything here, taking the time, and making sure that we can discuss a little bit more publicly.

We're discussing the format of that as well, whether it's an R&D Day or if it's a series of calls and experts with us. So sight just for a bit, and you're going to be able to talk about that.

We are very excited, both scientifically, on the patient side, and market potential for either of those indications.

That's all the time we have for Q&A at this time. I would like to turn the conference back over to Mr. Marcio De'Souza for any closing remarks.

So thank you very much, everyone. I'm sorry for the questions we couldn't take on today's call. I think we're running a little bit ahead here. An incredibly exciting way to start the year.

As you think back over the last 12 months, so much happened in really moving the needle for so many patients. Yet, another study they're finalizing, making sure that we flip the card, make sure that if there is a benefit, we're going to get that as quickly as possible.

This year, with EMBRAVE Part A being positive, EMBRAVE 3 recruiting really well, EMBOLD coming up, POWER1 coming up, POWER2 coming up, new indications, as Brian just asked. So we're full steam ahead.

The focus is very clear, is to deliver as much value for everyone, including our shareholders. And we promise you we'll have our heads down on the execution here and get everything done.

Thanks for the interest, and we're going to be talking to you soon.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.

Thank you, everyone, for joining us for the Praxis fireside chat here at the TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral, and joining us from Praxis, We have Marc -- come back, Marcio. We have, to my right, Tim Kelly, CFO, and Marcio De'Souza, CEO, who I'm sure you guys all know. Let's start right away. I know right.

Well, thank you guys for doing the breakfast this morning. We were really able to get into some of the nitty gritty, and we'll just keep briefing off of some of that. But let's start sort of higher level. It's going to be an enormously busy year for you guys. We'll start with the main driver is Ulixa for Essential Tremor, but you have NDA submitted both for that and Relutrigine. You filed as we started off this morning at breakfast, you filed and will not be requesting priority review. So you are anticipating for Ulixa, a standard review process. Can you remind us of the factors that guided this decision and especially addressing keeping your relationship with FDA as strong as possible?

Perfect. The multiple factors, right? I think there's a major economic factor here that has definitely drove a lot of the decision to file earlier this year, the NDA as a standard review and the fact that, we strongly believe with the market being as large as it is for Essential Tremor, addressable at launch over 2 million patients at peak, much larger than that, that it would eventually be subject to the IRA mandated negotiations and so on. And at that point in time, which is anywhere between like 7 years for the negotiation, 9 years for the full implementation, as we all know, it would be pretty close to the peak of the drug, if not at peak. And therefore, the impact of the negotiation will be the highest one would have in terms of revenue.

By the current negotiation calendar -- by calendar year of the approval. So an approval in December, takes 1 year away from the negotiation. So it's very important for us to preserve that since it would come pretty late in the year. So it's more economically viable to do it in the beginning of the year.

I think the second that you touched upon, which is quite important as well, why we take a different view of what's happened on the FDA than most people out there, meaning a less dramatic view, right? We actually believe that for the most parts, it's been pretty similar to how the agents operated before. In our specific case, has been, I'm going to call peaceful, meaning as expected, several meetings, several discussions, 2 NDAs filed, as you just heard. We are very cognizant about the reduction in the staff of the agency. And particularly, when you think about the Office of Neuroscience and the Division of Neurology 1 and 2, there's a lot of applications. There's a lot of stuff on the review. So when you put the two and two together here, the fact that it economically make a lot of sense for us and then from the agency, its just simpler. That was the choice we made to preserve these on both ends of the spectrum.

Investor focus has obviously been on staffing at the FDA and meeting time lines. In your review team in particular and in the division, can you talk about turnover or any change in leadership and change in your work -- main relationships?

Yes. So ulixa or ulixacaltamide, as we call ulixa internally is on [ GN1 ]. It's being always on [ GN1 ]. All the movement disorders are on [ GN1 ]. The -- since the end of Phase II meeting was in June 2023 until today, there's no change in staff, which is kind of important. I wouldn't say it's as fundamental as a lot of people talk about, but it's quite important to have continuity. We had very recent interactions, meaning like December interactions with them outside of the regular interactions like submitting the NDA, receiving the acknowledgment letter and the other things like formal meetings. And it's good to see the same faces. As you probably know, at the pre-NDA meetings where kind of first time meets the entire review team, right? It's a little bit of -- we don't know who are the review team to that point, a couple of people.

It was good to see that was really everyone kind of renewed from previous interactions as well. So very good continuity on that. On the [ DN2 ] side, that is the epilepsy part of the business, there was one change last year. You probably know Dr. Lee left the agency. The good news, I would say, for us is that the replacement was actually the Director of [ DN1 ].

Sorry, Dr. Lee is...

Paul Lee -- Emily [indiscernible] being on board. So now she's [ DN 1 and DN 2 ]. So in a sense, increases the interactions with the same person with the same overall leadership, allow us to understand a little bit more what they're looking for, how they're operating. I would say, for the most part, on any major requests, they met or exceeded the time lines getting back to us. And from time to time, there was a few day delays, which I actually consider -- I definitely do not submit all my expense reports on time. So I understand when there are a few like documents that don't get returned to us on time, if they are not consequential, like things that can take a little bit more time, but nothing consequential has been delayed. So I don't know if it's luck or if it's really the actual division, but I'll take either. And definitely, our experience has been quite positive.

So your NDA submission included the standard titration schedule from Essential3. But you also requested that the approval be for clinicians to maintain the 20-milligram dose for an extra week if -- if tolerability issues were seen. So this is sort of like a suggestion to hold that 20 milligram for an extra dose. Are there any other titration schedules that are alluded to in your work -- and is this a labeling discussion? Or is it like a material -- a review issue for the mid-label? Like will you have clarity on this by the time of the mid-cycle review?

Likely. So maybe it's important to reflect on the genesis of the discussion, right? So when you give ulixacaltamide to a patient with Essential Tremor, 7 out of 10 of those patients do really well during the titration, from a tolerability perspective by week 2. By day 14 is the first time we assess their tremor impacted in their life, and they are basically at full efficacy at that point in time. If you look into the results we've shown publicly, you're going to see more of that at [indiscernible]. So very fast, very effective, relatively safe since we always call generally safe before a drug is approved, right, in the U.S. at least.

For about 30% of them, the impact of dizziness can be problematic from a tolerability perspective. And some of them are discontinued the drug because of that, not because they're not in the way or getting efficacy, but because of the tolerability. So when we were with the agents, the discussion was kind of we like the fact that the vast majority of the patients have good tolerability and good efficacy. But it would be ideal in a population that is completely underserved, right? Really nothing works here from a pharmacological treatment perspective, to extend to its maximum, the ability for patients to respond.

And the agents had suggested that we should think about it maybe for later in the future, after approval to do something. But we have a fair bit of data from the Phase II study and for patients who didn't discontinued the treatment, that gives us the, I would say, knowledge, of course, impression on the case they have to review that keeping the patients at 20-milligrams would actually resolve this for virtually all of them. So we had this discussion with the agency. They said, well, if you believe that, that would suffice for us to review, including the submission, including the proposal and the label, which we did. We included in submission, we include the proposal and the label, and we included a new titration pack as an alternative form, in case that happens. So this is going from 70% of the addressable population launch to like close to 90%, 100% depends on how it's going to look.

So it's our joint objective as a company, and the FDA to try to help as many patients as possible here. Now it's always a matter of review, right, to the last later part of your question. So the agent is going to review, they're going to agree or not, going to have a discussion or not. But it's a fairly solid scientific proposal and would be ready to support that.

I think the only thing, -- if I can just add quickly, too, this is an issue of tolerability, not safety. I think that's a really, really important distinction in there. And one of the things that you don't have a chance to do in a clinical trial setting is for a physician to interact with the patient, say, this is what's typical of this drug. Here's how you're going to feel. If you don't feel great, call me.

That doesn't exist in a clinical trial setting, but it does in the real world. And so I think that's going to also be part of our launch and our medical communication as well that we're working with the physicians on how they can best administer ulixacaltamide also.

One of the things that we've discussed with KOLs is the idea of the daytime dosing, like the fact that in the trial, the protocol demanded daytime dosing. So as we think about like dizziness and brain fog, is nighttime dosing just something that patients and doctors can just do? Does it need to be -- do you want it to be part of the label? Can it be helpful?

So it was done exceptionally in the clinical study and mostly for shift workers, since we actually dictated morning, as you said, or under approval of the sponsors. And we did approve a bunch of those during the study. So we do have actual data to substantiate, if that is the request from the agents. This is the kind of thing that physicians, as you are hearing, you're incredibly comfortable in making the choice themselves, even if it's not the exact recommendation, [indiscernible].

Prelaunch activities. as we discussed this morning, they're well underway. What specific operational milestones need to be achieved over the next 6 to 12 months to ensure that you are fully ready for the Ulixa launch? We're talking disease awareness? Are we talking about endpoint awareness, like the meaningfulness of the endpoints? Is it prescriber identification, the index of suspicion about who your sales force is going to target and then obviously, sales force hiring, buildup, et cetera.

Yes, I would say -- take a shot, I think the answer is yes.

All the things.

Exactly. We are very excited about the potential of the drug, but also there's a huge amount of work to go into ensuring it's successful. I was an economics undergrad. So I think in terms of supply and demand. On the demand side, we have talked a lot about how we identified over 200,000 patients with Essential Tremor interested in participating in the clinical trial over the 15-months, when we were doing the recruiting. We want to get that number up to be multiples of that by the time we get to launch.

And so things like disease awareness or the type of activity we can continue doing, we were very successful with a particular form of targeted advertising, we want to maintain and not really invest in quite a bit more so that by the time of launch, there's even more patients who are aware that there is a therapy for disease that...

So DTC disease awareness in advance of the launch?

We call it GSC, but yes.

What is DTC...

Like dizzy state, like education and all the parts that's done right now, after AAN, I didn't mean to interrupt, Tim, and then you pick it up again.

After AAN next month, you're going to see our GSC platform really taking off, like AAN is like a device...

Am I going to get like the Instagram target...

You will...

But yes, you can see how important that is. And what we found in the study is the average patient had the disease for 30 years. And so if you can imagine that, that's now a lot of what people have accepted in our life and to say that there's something coming, that's a really important activity for us to build up that demand.

On the supply side, then we've got the medical community. And it's not only the physicians who we need to ensure we're targeting and finding the right ones, educating them. That's why AAN is so important for us. We're starting with neurologists, and that's where they're all going to be. So a hugely important meeting. But we also need to work on ensuring that the pharmacies are ready, that the channel is ready, that we're preparing things like Patient Hub Support. So we're putting all of these things in place.

Will you do specialty pharmacy distribution? And what's the parameter of the Patient Assist Hub that you guys are thinking?

We'll tag team this one. I think given the -- and we'll probably talk about pricing in a moment. I think given where we're looking at pricing that a specialty pharmaceutical -- or pharma channel does look appropriate for it. And then in terms of hub, we want to ensure that patients are not having any issues. If there is step through, we've conservatively assumed that all patients will need to step through for [indiscernible]. So we want to be sure that, that's streamlined any issues they may have with prior authorization. We want to be ready to go and proactive so that this is a very positive experience for them.

When you look into the scale of this launch, right? So imagine that nothing changed between now and the time of launch, in a few months. There are about 1 million patients being seen by neurologists every year in the U.S. for Essential Tremor prescriptions, not treatments, just to actually get prescription for something. It's about 1 million that was just seen. So nothing else. Markets don't stay static, but ignore that for a minute, take that 2 million patients that are like seeking treatment right now and then apply, whatever assumptions you want for the first quarter of launch. It's a large volume of patients.

I want to make sure they have the best possible experience getting ulixacaltamide. That's why, Tim was just mentioning, we're going to do, I would say, special pharmacy and hub support can be completely full white glove, like as you do in a gene therapy for a rare disease.

Which you'll do for like...

Relutrigine. It can be a middle of the road where you're actually taking all these barriers away. We're helping the office when they need, but it doesn't burden the system as much either. And that's where we are picking right now, the design. And that is going to facilitate the launch without creating an extra financial burden on us or in the system or on the physician, that is prescribing.

When you're testing this with providers in general, they think this is great, and facilitate dramatically how they're going to get these patients in. But it also gives us control of the experience, which is quite important on the first few months of launch, right? There is no neurologist in the country who has one patient. This is not the kind of disease that it goes like, oh, I only have one patient. They have 10, 20, 30, hundreds. Some of them have hundreds of it, they just see. So we want to make sure those first few patients are really going really well so they can maximize the drug.

Because when we ask physicians having advisory boards, having a lot of research, being done with them, because the data is so consistent amongst all the subgroups, a priority, they don't have a way to pick what patients would respond. So the conversation we're hearing back from physicians is like, I will talk to all my patients about this drug. It becomes even more important to have the proper parameters education, when that is the kind of launch we're going to have.

Right. So how should we think about this? Because like myself, I think -- or Athena, we're going to be breaking out your 2027 quarters pretty shortly. So as we think about out of the gates, how do you think about going broadly and doctors wanting and having a lot of patients to go to, but also tightly controlling for a good experience so that the reputation of the drug is positive. So you filed in February. We're thinking standard review. How should we think about 2Q, 3Q, 4Q of '27? Do you want to limit it? Or are you just going for it?

No. That's why we're putting a little bit of this -- we are building expectation in a sense maybe more than we should around AAN, right? So AAN is the first time, number one, the data is going to be presented in a scientific audience, right? So we have multiple presentations at AAN. AAN is the most important neurology meeting in the country, arguably in the world. Virtually every large practice or important neurologists in the country is attending. It's a really concerted effort to get the first wave of knowledge of the data, which exists in several thousand now, but not only 13,000 or so thousand neurologists that would be the target at launch.

From that point on, there is a split. There is a lot of towards patients and I would say, reactivating patients, which we did quite exquisitely for the clinical study. So we think it's more, a build on what we've done before, was a lot of builds with the physicians, right, for the MSL conversations, for leadership conversations and just general education between the next quarter. I think when we turn to Q3 and Q4, then there's a lot more certainty on the timing of the approval, right? That's beyond or around mid-cycle call, like we'll have an idea -- that's where the deployment becomes like full force towards really the kind of support is going to be given, education. That's where the last payer discussions start happening as well.

The last payer discussion?

Absolutely. Like that is a little bit of a misunderstanding. Most medical directors and payer systems don't even get you through the door, if you don't have a PDUFA defined because it's a waste of their time, right? So you'd have preliminary discussions right now. We have reasonable discussions when the PDUFA is given, which is soon for us. But we really don't have discussions until they run their numbers on their claims and then you can sit down and talk about impacts and everything else, which...

So you need a PDUFA rather than the label to start discussions?

Yes, we absolutely don't need a label to start discussions. To launch a drug, we're going to need the label. But that's -- in a sense, it's too late to have the conversations with most of those entities. And then, of course, after launches, full deployment, commercial campaign, then we're not talking about educating anymore, about the disease or a potential. We're talking about what is in the label and what's consistent with the label since that's the current legal standards, consistency with the label.

So you mentioned pricing. Does that mean you're -- what price will -- give it a whack today?

Yes. There's still definitely a lot for us to be looking at. I think what we have been considering is, you're looking at a price that reflects the innovation of what this drug is, the great data that we saw, the safety that it brings as well. I think we have a good analog when we look at some of the tardive dyskinesia drugs who are kind of at the low 6 digits. We've got a lot of range.

If we want to go that high, we definitely probably could. I think there's a place more in the midpoint to say as a starting point, that gives us a place that -- a good place to start from. And I think when we go into a future world with IRA, the way discounting is probably going to be done, it's better for us to start at a higher place where data can inform, if we need to take any discounts rather than start low and expect annual inflation increases. Those days are probably waning. So we look at a little bit more, at that midpoint to start.

And thoughts on the size of the sales force?

When you do -- we did preliminary sizing, I'm going to do like final sizing now we just refreshed our -- you asked the question before, we didn't properly address. Because this market has been, from a patient perspective, established for so long that for a drug, there is no drug, you can literally map patient to NPI, right? So you know who has been seeing these patients for the last...

NPI is...

Like the identification number for any prescribing physician. Chart is there, has one. Everyone here who is prescribing, has their number by heart...

You're so on, right there.

That's what I call out because he's a practicing neurologist. And so you can just go and run these numbers. This is public. Well, we buy them and you can just see. So we know who has been seeing these patients because we're not going through -- as you know the disease, we don't know. So we have to run these algorithms to extrapolate. Here's pretty simple. It's a one-to-one relationship, antisense ICG-10 to an NPI.

So we know the concentration. The number would say that we should stay around 200 or so to cover well. The country, we will go higher than that. And it's a little unusual for companies to say they're going to go higher at the time of launch, but we're going to go higher for multiple reasons.

One, there are a few adjacent, like very large practice outside of neurology that need coverage. So one. The two is, we wouldn't want this launch to be limited by not being able to generate the demand on the prescriber perspective. So we've seen multiple launches, particularly in neurology, where the company takes the opposite approach, right? So we need 200, we start with 100. And then in quarter 1, it's 125. And quarter 2, it's 200. And you're always chasing the market versus actually rightsizing for the success case. So you should expect 300 or so that would cover well, the U.S. would cover well.

And are you going to hire them earlier so you can deploy them for a disease awareness? Or is this sort of like a conditional offer upon approval, PDUFA date?

So the beauty of all here is that we have some flexibility with both drugs, right? And...

And also your balance sheet.

Well, yes, but we're always very careful with the -- because money is there until it's not. So you have to continue being incredibly responsible. I think it's important to properly invest. But at the same time, the more the certainty increase on the timing, it's not if, it's when, for the approval of these drugs. that we can deploy more and more, but it can be sequential. So we don't have to do a one size fits all here. You're going to see a lot more people in the field before for us and then a few months before launch, it has to be fully deployed. You can't wait for the day that you have certainty to actually deploy, it's too late.

I do have to spend a few minutes on relutrigine because that one is going to get approved first. And with the priority review also filed, so that PDUFA is probably Q4. Are you currently building out the rare epilepsy sales force? We talked at AES about a separate targeting effort. Do you need to build disease awareness here? And how much do you have to address this issue of the utility of stacking sodium channel drugs in this population? Because like you weren't supposed to be able to do it at all. Some people said it was going to make it worse and now it's making -- anyway?

Here we are. And we are wrong again in cycles, right first time. The -- it's not an issue whatsoever. I would say patients did really well in this study, both on safety and on efficacy. So I think if anything, the community is incredibly excited about this, very different dynamic that we're discussing on ET, very, very different dynamic.

So there are two major drivers here. So one is the number of centers differently from ET, very concentrated. So about 10 centers in the U.S. -- are a referral for the patients. So they're very well characterized. They don't see all the patients, but they definitely consult on a lot of those patients, a very good relationship with pretty much all of them.

And that's all you need to target those 10 centers?

That is not all we need to target, but definitely, they are the ones that between now and midyear, we spend most of the time. So they have all, like the understanding of the data and most of them have already. It's just like complementing a little bit.

Then the second wave is really the community neurologists that been caring on the day-to-day for these patients, right, pediatric neurologists, particularly just connecting with them. There's always a smaller number. It's only a few thousand patients, like 5,000 to 10,000 patients addressable at time of launch here.

For the SCN2A?

Yes for SCN2A, and then the last one after that, patients who were born in the last 10 years in the U.S., which are most of the addressable here, they all have genetic diagnosed. There's like sometimes people talk, oh, the identification is being pretty much solved in the U.S. right now. But the previous ones don't.

So really getting that referral to make sure they get diagnosed, that's the second wave of the launch. It is important that we start earlier as well. So we know you're responsive to certain sodium channel blockers. So it's likely, but you haven't done a gene panel, it's important for that as well. We do see -- when you, in this case, triangulate medical record, EMR with other data that there are far more patients that don't have the final. We are not currently including them on the TAM, but...

The final genetic diagnosis?

Yes for the 8A. And then most importantly, right, it's like we're running the EMERALD study. It's going really well. That will expand the market fopr the larger deal...

And by how much?

By 20-fold.

20-fold. And that's going to need expansion of the sales force at that point?

Yes, absolutely.

Next data catalyst is POWER1, though, and that's vormatrigine for focal. That data is due Q2. Let's talk about expectations around what median seizure reduction rate you're going to show with top line and what your expectations for placebo are?

If you look into the last 10 years or so of epilepsy drug development, not the narrative, the actual data, it's been pretty stable, placebo, and it varies anyway between 0% and 20%. 20% is probably the most conservative someone should pick, and that's why we picked. That's why others pick as well to calculate. So I think that's a good point to start with a drug showing anywhere between like, I would say, double of that to -- at the lower end to triple of that on the higher end. So anywhere between 20% and 40% -- 40% and 60%, sorry. I don't know basic math. That would be a reasonable here. So we use 30% placebo adjusted as the target. But nothing wrong.

I know others in this space have been talking about their drugs that read out soon possibly being as low as 40%. I don't think it's a problem actually. I actually think I agree that would be a good benchmark for them and it's a good benchmark for us. But everyone is looking for the 50s as they go to here.

Very large markets, like over 2 million Americans with [indiscernible] seizures, the majority of them by far having breakthrough seizures every year, not a minority as some of the literature tends to refer to. In our very extensive research using Electronic Medical Records, claims analysis, tokenized data, it's over 60% of the patients that have breakthrough seizures, require medication change in a given year. So 1,2, 3, 10 drugs new in this space, they all do really well. This looks a lot more like DMS markets than the historical epilepsy market, where there's a space for several drugs, several modalities, several ways to do it. We just think, very excited about the new wave of epilepsy drugs in development, but particularly for vormatrigine.

Great. Last question, I can't forget about Elsunersen. That Phase III pivotal is ongoing. How is enrollment going?

Good. So you might recall that last month, I guess, last quarter now, passed very quickly.

The FDA suggested we remov the sham, was originally sham-controlled. They strongly suggested that we removed, we actually strongly agree with them, and we removed the sham from that study, made an emergency amendment to the protocol, so the patients could be switched and it's going well. We also have a proof-of-concept study, I would say, proof-of-concept plus reading out in Q2, which has 9 additional patients on a sham-controlled cohorts that we've done. That would further, in our view, de-risk this opportunity for elsunersen between later in the year, beginning of next year, we should have the results of the Phase III. So we'll be filing for another NDA, hopefully, in the next 12 months as well.

Great. With that, we are over time. Thank you, Marcio, who wasn't supposed to be here.

Thank you, Ritu.

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2025 Earnings Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Dan Ferry, Investor Relations. Please go ahead.

Good morning, and welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2025 Financial Results and Business Update Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com.

Please note 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 time lines and financial projections. While these forward-looking statements represent Praxis views as of today, they 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.

Joining us on today's call are Marcio De'Souza, President and Chief Executive Officer of Praxis; and Tim Kelly, our Chief Financial Officer. After updates on our key programs, we'll move to a brief Q&A session, where Marcio and Tim will be joined by Steve Petrou, President of Research and Development; and Megan Sniecinski, Chief Operating Officer. With that, it's my pleasure to turn the call over to Marcio.

Thank you, Dan. Good morning, and thank you for joining the Praxis Fourth Quarter 2025 Conference Call. Let me start by saying that 2025 was a remarkable year for Praxis. It was marked with the breadth of significant clinical achievements and regulatory advance across our portfolio with positive readouts and FDA interactions for ulixacaltamide, relutrigine and vormatrigine as well as accelerated development plan for elsunersen.

Standing here today, we deliver on our goal to submit two NDAs one for ulixacaltamide in essential tremor and one for relutrigine in SCN2A and 8A DEEs. Just like 2025, this year will continue to enhance our clinical portfolio and mark our transformation into a commercial company.

Next quarter, we expect to have the top line results for POWER1 for vormatrigine in focal epilepsy and the elsunersen EMBRAVE data. In the second half of the year, we expect to complete enrollment for POWER2. The EMERALD trial for relutrigine in broad disease is expected to serve as the base of an sNDA by next year. And those are only a fraction of the deliverables expected in the next 12 months. We have the drugs, the people and the capital to deliver yet another transformational year, bringing innovative treatment to patients with CNS disorders.

Let me now deep dive a little bit on each one of the clinical programs. Now focusing on ulixacaltamide. Last October, we reported the positive top line results from the Essential3 program with both studies delivering clinically meaningful and statistically significant results. Study 1 met its primary and all key secondary endpoints with ulixa showing meaningful improvements in the mADL11 in the rate of disease progress, PGI and CGI. Study 2 also met its prespecified primary endpoint with ulixa demonstrating a superior maintenance of effects during the randomized withdrawal phase.

This was the first time an investigational therapy designed specifically for patients with ET showed positive results in a comprehensive clinical program. Based on this positive data and the fact that there is no other specific therapy delivering such results as ulixacaltamide, we have granted breakthrough designation by the FDA in December. Had a very productive pre-NDA meeting in December with the FDA and worked diligently to prepare the NDA submission. We have recently completed the NDA submission to the FDA.

Now as we move towards expecting an approval in the near future, our preparations for the commercial launch for ulixacaltamide are well underway. We estimate that more than 7 million people in the United States live with essential tremor with about 2 million of them being an immediate need for therapy or an addressable population, as we call. And we're excited about the opportunity to deliver a therapy that can meaningfully improve their daily lives. As we interact with more neurologists in this space, we continue to hear this a drug that meets a large unmet need in their practice and their interest continues to improve towards the potential use of ulixacaltamide when available in the future.

We believe ulixacaltamide has a big potential of over $10 billion annually. Given the size of the population, the strength of the clinical data, the opportunity for responsible pricing that recognize the value of the drug, we have been building our commercial organization infrastructure, including key hires and core aspects of the prelaunch plan, including preparing a comprehensive medical education campaign, which we plan to launch at the upcoming American Academy of Neurology Annual Meeting in April. At AAN, we also share additional data from the Essential3 studies in multiple presentations. We look forward to interacting with our core IDNs in Chicago next quarter and share the exciting data from the Essential3 program.

Moving on to our epilepsy programs. We started the discussion with our relutrigine program in developmental and epileptic encephalopathies, a group of severe epilepsies characterized by developmental delays with early onset for which there are limited to no currently approved treatments. In December, at the Annual Meeting of the American Epilepsy Society, we presented data from the EMBOLD study in SCN2A and 8A DEEs. We delivered overwhelming efficacy with relutrigine treatment leading to a clinically meaningful and statistically significant change in seizure and associated developmental endpoints like disruptive behavior, alertness and communication. Beyond the impressive overall results, the effect of relutrigine was rapid, durable and continue to deepen with time.

Given the strong efficacy results and the favorable safety profile, underscoring relutrigine best-in-class potential and alignment with the FDA, we have submitted the NDA earlier this year. It's worth mentioning that relutrigine has rare pediatric drug designation, making it eligible for the pediatric review voucher program upon approval. The initial addressable population for relutrigine for SCN2A and 8A DEEs is roughly 10,000 patients in the U.S. However, there are currently over 200,000 patients with DEE for which we believe relutrigine could offer benefits.

The ongoing EMBOLD study is assessing relutrigine in the broader DEE population and we are on track to complete enrollment in this study this year. If the NDA in SCN2A and 8A we just submitted is approved and the EMBOLD study is positive, we expect to submit a supplemental NDA for the treatment of broad disease by 2027. We believe the full potential of relutrigine in DEE space could be as large as $5 billion in annual revenue.

Similarly to the efforts for ulixacaltamide in essential tremor, we have initiated prelaunch activities, including key hires and building sufficient inventory for a successful expected launch of relutrigine. Our team has been accelerating the efforts to ensure patients have access to this potential first disease-modifying treatment for SCN2A and SCN8A.

Moving on to vormatrigine. Our comprehensive ENERGY program for vormatrigine, a next-generation functionally selective small molecule in development as a once-day treatment for adults with common epilepsies. At the December AES meeting, we shared the full data from our RADIANT Phase III study, where vormatrigine demonstrated its best-in-disease potential in patients with focal onset seizures. Vormatrigine had fast-acting efficacy with 58% of patients achieving at least 50% reduction in seizures at week 1 without the need for titration. This effect continues to increase with patients who proceed to the OLE were achieving 100% median weekly seizure reduction at week 9, which was sustained through week 16. Additionally, we saw the vormatrigine improved efficacy on top of other common antiseizure medications patients were taking.

We are on track for multiple readouts from the pivotal studies for vormatrigine in the next 12 to 18 months. The next clinical update will be for POWER1, our study in focal onset seizures, which exceeded its original enrollment targets. We expect to share the top line results in the second quarter of this year.

The second Phase III study, POWER2, has been enrolling patients and we anticipate enrollment to be completed by the end of the year. Those two studies, if successful, will serve as the base of a new drug application for vormatrigine. We're also on track to initiate the POWER3 study, which will evaluate vormatrigine as a monotherapy in the first half of this year as well.

Altogether, it's a very robust registrational program that we believe will demonstrate vormatrigine's potential to address the significant unmet needs of approximately 3 million people in the United States suffering from common epilepsies, potential to achieve over $4 billion in annual revenue.

Turning on to our fourth program in the clinic, elsunersen. Elsunersen is being developed for the treatment of gain-of-function at SCN2A DEE, a rare genetic epilepsy characterized by early onset seizures and very detrimental developmental impact. This past December, we have had a favorable meeting with the FDA where the agency agreed to update the EMBRAVE3 registrational trial design, simplifying it by converting from the double-blind sham control design to a single-arm baseline controlled study where approximately 30 patients will be enrolled. We are quickly enrolling this study and expect it to be completed later this year with a potential NDA for elsunersen next year.

While EMBRAVE3 is enrolling, we'll have some additional data from the EMBRAVE study Part A, our Phase I/II study evaluating the safety and efficacy of elsunersen versus sham procedure. The trial is ongoing and are on track to report the top line results from the original nine patients in the first half of this year.

Elsunersen also has rare pediatric drug designation and we qualify for a pediatric review voucher upon approval. Once approved, we believe elsunersen has the potential for over $1 billion in annual revenue.

In summary, 2025 was a year of major portfolio advancements as we enter our pre-commercial phase. We started 2026 strong with two NDA submissions, and we're positioned for another catalyst-rich year with multiple readouts of our innovative pipeline.

We are planning an R&D Day next quarter to discuss our clinical programs and preclinical programs and a commercial day to follow where we highlight our launch strategy, readiness and more aspects of the launch for ulixacaltamide and relutrigine.

With a very strong balance sheet, we're well capitalized and focused on discipline of execution to deliver on the preclinical, clinical and pre-commercial activities this year to come. while unlocking the more than $20 billion of opportunities across our comprehensive CNS portfolio.

With that, I'll hand over our call to our CFO, Tim Kelly. Tim?

Thanks, Marcio. Good morning, everybody, and thank you for joining today's call. I'll provide a quick summary of our fourth quarter and full year financial results. 2025 was a year of continued investment into the pipeline while maintaining rigorous financial stewardship. In Q4, operating expenses totaled $97 million, broken down to $77.5 million for R&D and $19.5 million for G&A. That compares to Q4 of 2024, where total operating expenses were $71.4 million, broken down to $56.3 million for R&D and $15.1 million for G&A. For the full year, operating expenses totaled $326 million for 2025 compared to $209 million for 2024. The increases in both Q4 and full year were driven by an increased spend in our Cerebrum and Solidus platforms to progress the portfolio of clinical programs. As we go into 2026, we expect to have a significant increase in spend as we invest into our commercial launch activities that Marcio just discussed as well as continuing to progress the pipeline.

We ended Q4 with $926 million in cash, equivalents and marketable securities compared to $469 million as of December 31, 2024. This increase of $457 million was primarily due to net proceeds from Praxis October 25 follow-on public offering and net proceeds from the at-the-market sales of common stock offset by cash used in operations. Our cash position was further strengthened through proceeds from a public offering in January this year, which yielded $621 million. When added to our year-end position, our pro forma cash is approximately $1.5 billion, which is expected to fund operations into 2028.

With that, I will pass it back over to you, Marcio.

Thank you, Tim. We're going to now open the call for Q&A. Shannon, would you compile the queue, please?

[Operator Instructions] Our first question comes from the line of Yasmeen Rahimi with Piper Sandler.

Congrats to the outstanding timing of the filing. So congrats. Two questions, one directed to Tim and one for Marcio. Tim, if you could maybe walk us through the pre-commercial activities that are going on currently and what the cadence are going to be throughout 2026. That's very helpful.

And then for Marcio, maybe help us understand sort of what additional new data we could be seeing at AAN, and I'll jump back into the queue for respect to my colleagues to ask questions.

Yes. Thanks very much, Yas. And glad to be talking about what we're doing to prepare for two launches. As you can imagine, we're at the stage now where we're making some key hires and looking to build out the talent for our commercial organization. We've also been focusing on ensuring that we have sufficient inventory for what we expect will be good strong launches, and we never want to run out and be sure that we've got inventory on hand for all scenarios. That's a long lead time activity, so very well in hand to ensure that, that's in good shape.

And then also looking at for -- particularly for ulixacaltamide, helping to improve awareness of the disease. And Marcio in a moment will talk about our activities at AAN and all the data we're sharing there. We're also looking at that at a time when we can start sharing more about the disease and help patients understand about the innovative therapies we're developing.

Yes. Thanks, Tim. That's a lot going on, as you mentioned, right, in terms of making sure that not only the highest quality NDAs were submitted as, of course, was always our priority, but now moving on to making sure a smooth review with the agency. And then on the other side of that, the prescribers really understand or potential prescribers really understand the disease in one hand, which they understand well, but there's obviously a good reminder there. And on the other hand, the clinical data for ulixa and then relutrigine later in the year as well.

In regards to the American Academy of Neurology meeting next quarter, we have about 15 different presentations going on at the meeting. It just speaks about the number of things across the company. A number of them are about the Essential3 program and essential tremor in general. What we're going to be doing there, as you will see, and I hope to see you there in Chicago is oral presentations on the clinical data. AAN actually is very nice for that because the presentations are reasonably long. So we can go into a fair bit of detail on the clinical program, which, of course, very important for the 13,000 or so neurologists that are our audience. They're going to be there also to expand the understanding on the overall community of this very strong clinical data set.

So we're going to be discussing like other aspects like the response on the drug and what happens to these patients and just how meaningful it is the combination of all the endpoints, but particularly the primary measure here that's the mADL11. And you're going to see throughout all the presentations, there are very robust number of new data points. We put a lot out there. So it's not to say that there is any scarcity of data on the Essential3 program, but it is definitely more geared towards the future prescriber here that is the neurologist. So incredibly excited, very grateful to the scientific community of AAN to giving us the podium there to present the strong clinical data.

Our next question comes from the line of Ritu Baral with TD Cowen.

This is Athena Chin on for Ritu. I have another one on ulixa. You previously indicated that the label may include alternative titration schedules. What is the status on this? And are you currently running additional studies to support this? If the label doesn't include these schedules, how will you be educating and guiding prescribers upon launch? And then I have another follow-up.

Yes. Thanks, Athena. So maybe I'll break it down, if I may, your questions in two parts, right? So we've been discussing since you asked about education. And surprisingly, I would say there's very little education needed here. We've been presenting the data for advisory boards for consultation meetings to a number of key opinion leaders in the country, very top key opinion leaders. And it's very clear that they see this incredibly robust and very, very easy to deal with the potential tolerability for a subset of patients here that we know might have that.

Now going back to the matter of the label, as we previously discussed, we proposed not only submitted proposed label to the FDA, not only the standards titration that was done in the clinical study, right? So seven days 20 milligrams, seven days at 40 and then seven days at a stable dose of 60, but also an alternative that we discussed with the FDA.

I think as we move forward, as we continue to engage with the agency here, it's now their view has to prevail in terms of what the final label is going to be. So it would be pretentious to us to say what's going to happen there. But it came in the heels of discussions with them and alignment. The agency was incredibly clear with us that they did not expect us to conduct clinical studies preapproval on this regard. So as we always respect the opinion of the FDA and the guidance they give, of course, we're not doing. I believe, and now that's my interpretation, that is because this is really not a safety issue, right? That is some tolerability that happens on a subset of patients. It's very quick. It resolves very quickly. And the efficacy, most importantly, is very strong.

So when you put from a benefit risk perspective, that is both our interest, the prescribers' interest and the agent's mandate that is all maintained quite nicely. We're going to see how this progress during the review, and we're very enthusiastic about the ability to have serving not only the 70% or so of patients that stay and do really well, but hopefully 100% of the patients that try this drug.

Got it. And as to the commercial prep for both relutrigine and ulixa, how much capital allocation should we be thinking about between the two programs?

I think in terms of allocation, you can imagine that with ulixa being a much broader market, we will be probably putting more of the allocation there. I think we're looking at, as I said, the disease awareness campaign, probably a bigger field force as we get into that part of the work as well. The inventory build is going to be a bit bigger. So we want to be sure I go back to the old line, you only get one chance to launch a drug, and we want to be sure we're investing appropriately for a great launch.

I think with relutrigine, when we look at that market, particularly focused initially on the 2A and 8A population, it is a bit more focused. So there's a lot of disease awareness for us to be. Doing there. It's a more focused effort though with those physicians, but we want to be laying the groundwork for the indication expansion that we hope will come in 2027 with the EMERALD study. So it's a bit of a strategic move on how we will do the commercial prep for relutrigine also.

Our next question comes from the line of Yatin Suneja with Guggenheim.

I have two questions. With regard to the POWER3 study, can you just articulate to us how will that study help you move towards the frontline setting or to in FOS. So that's one.

And then the second question is around the review time line. So we -- I think, Marcio, it will be good if you can address the review time line for both the NDAs. We do get questions from investors in terms of priority review or not. So it will be good to sort of address it today.

Yes. Thanks, Yatin. So starting with POWER3, right? So just a reminder of what we are trying to accomplish here. So POWER1 as the like first study here for -- towards registration for vormatrigine reading out as we just narrowed here in Q2. The study enrolled a fair bit more than the original 230 patients that were planned. So we're very, very happy with how enthusiastic the investigators were on enrolling patients on this study, particularly like when you consider competitively how well this study enrolls, right? Power2, as we're enrolling quite nicely right now as well, would be the second registrational.

But when you look into the market, and it's something quite interesting what this goes on and on that features. You do have, I would say, a part of this market that is the more refractory patients or going to even argue hyper-refractory being super treated multiple ASMs really struggling for years and years, possibly decades here. And that's where most of drug development and most of what the Level 4 epilepsy centers, the key opinion leaders in epilepsy have been focusing.

But when you go to the rest of the market, and it's probably a little physicians to call rest because it's the majority of the market, right, the patients that are 70%, 80% of the patients with focal onset seizures, they still can strive. They still can carry on with their lives. There's all sort of restrictions because they're having like breakthrough seizures from time to time, and they're really not doing well. That market has stayed untapped until now.

So speaking with those physicians and people who treat a significant number of patients, right, which is a different subset of the ones we're looking. The need there is for a drug that they can trust and understand how to remove the treatments, so they can be confident and they are very enthusiastic about vormatrigine for that matter. So we've been in consultation with them finalizing the design. We're getting this off the ground very soon. We thought today was the day to reinforce and celebrate submitting two NDAs. So we're going to be talking about that more in the near future.

But what it does to the drug, while not required for registration, right? This is not a requirement as is the ever-evolving requirement for registration in the United States as we are seeing this week. So we're very excited about what's to come. But it is something we can see as moving to first-line potentially this drug in the future, which is from a serving patients is what we all should be aiming for. We're just in a very privileged position that vormatrigine might be the drug that allows patients and physicians to do that.

On your second question about the review time lines, you can imagine that the decisions we have to make are multiple fold, right? So, one, obviously, the timing of the submission is now in the past. The second is the entire understanding and relationship and workload and so forth with the agency. A good reminder here that DN1 or Division of Neurology I and II are two different divisions, there's a lot of shared resource. We're having two NDAs at the same time with them. Very obviously, relutrigine is easier. I'm going to say not because it's easier from a clinical or anything like that. It's just much, much less data by single study rare indication and that by itself from a workload perspective is smaller. So we decided to request a priority review for that application, but we decided not to request for ulixacaltamide for multiple reasons, right?

Those that I just mentioned, but there's a broader business reason about the time of the launch and the maximization of the revenues over time for this drug, particularly around PIC, particularly around payer and overall dynamics of discounting and so on that happens here later in the launch. So on a drug that can be and will be as big as ulixacaltamide, we can't like pick up the dollars and forget about the millions on this one. So I think we need to be -- and we were very focused strategically on the overall value here.

Our next question comes from the line of Joon Lee with Truist Securities.

Congrats on all the progress. I just want to clarify the response from the prior question that you just answered. So you mentioned business reasons for not asking for priority review for ulixacaltamide in ET. Just to clarify, is that because asking for standard review as opposed to priority review would result in almost a year delay in being forced to negotiate under IRA? That's question number one.

Question number two, looking forward to your presentations at AAN, can we expect any long-term follow-up data? The reason I ask is long-term efficacy came up as a key point for our payer KOLs regarding reauthorization of ulixa in ET.

And the last question is, in the past, you telegraphed around $50,000 list price for ulixacaltamide. Is that still the case? And can you help us understand your thought process behind the pricing strategy?

Yes. Joon, I think you are in the right direction there, right, in terms of when you're looking at and we're forecasting this drug. Of course, there are multiple dynamics, and you just named some of them, right, like what payers and reauthorization and like potential step edits and you name it, but the Inflation Reduction Act and the dynamics of the Act right now is an important consideration as always a very important consideration. This is a heavily Medicare Part D population. So we want to make sure we're both responsible on how we're launching. We're also maximizing and giving the proper value for the drug. And that includes looking to the life cycle of evolution of the current iteration of the act when it impacts, when it kicks in, I believe that's where you're going there. There's a pretty big difference in value depending on when that negotiation happens. And it was a key consideration on our filing strategy.

The second on the data to be presented, I think multiple fold, yes, we're always like going to be presenting more and more data to reinforce the short-term and long-term value of ulixacaltamide in essential tremor. One point we believe there's still room to explore here is really how strong the data is. I know you recently spoke to some payers and like payer groups. And they -- if I understand correctly, they agree with how strong this data is and how high the potential for this drug is. But it's what is the understanding is not clear yet in the market because we haven't put the data out there is just how deep the effect is on a very large proportion of patients.

And when you look into drugs, it's not one size fits all. So we want to make sure that gets reinforced, that gets holistically reviewed. While we're very excited about having our principal investigators presenting this data to their peers. They've been thrilled with the execution, with the results. And I think now is the time to let them take the stage and present this data as key opinion leaders in the field. So stay tuned. I know we're trying to cover a lot in this call, but stay tuned for April. I'm sure we're going to be pleased.

Our next question comes from the line of Andrew Tsai with Jefferies.

Congrats on all the progress. I appreciate the updates. Maybe shifting to relutrigine actually. You're pursuing this broader label, the EMERALD study for all DEEs. So how many different DEE patients in the Phase III does the FDA want to give you a broad label? And how many different DEEs have you enrolled so far? And secondly, for that study, as we think about what you want to see, is it fair that you might be expecting efficacy to be similar or even stronger than what you saw in SCN2A/8A and maybe explain why?

Yes. Thanks, Andrew. So, if you look into EMERALD right now, right, let me separate a couple of things there. So, one, as I mentioned in the remarks and then Tim mentioned as well in one of the answers, the goal here at this point in time is to get that sNDA by next year, right? And it should give you the confidence on what's happening on the study right now. Really incredible interest, incredible enthusiasm and engagement from the physicians that are referring to the sites or participating at sites in this study.

We took a very basic approach, right? If you go and you look into the most recent definition of these, Dr. Scheffer recently published around this and really going back to the basics, right? What is the developmental epileptic encephalopathy, what are the drivers, like what should we be treated? And relutrigine sits like on that junction of really helping the broadest population, at least hypothetically right now since we're going to have to see the results in DEE. So we took the approach of phenotypically defined versus genotypically defined these patients for this study.

What I can tell you right now without saying too much is that it is a very diverse group of patients that we have on the study, both enrolled studies and patients in screening, very diverse, not completely unexpected or unexpected at all. And when we position and we discuss this study with the agency, and I can never speak on their behalf, but I tell you our interpretation is that the idea here is to treat the disease, is not to treat the cause of the disease, would be pretentious to any of us to try to do that. And the understanding is that you cannot have a seizure without participation of sodium channel in the neurons. And therefore, this is like omnipresence type of mechanism that we can use. So that is the definition right now. There is no subgroups or there are no quotas for different, if I may, for different etiologies. So we're really looking into like an overall effect.

When you go back to the last part of your question, and what to expect here. We need to go back to translation. We need to go back to the preclinical data since we do not have the clinical data yet. And when you go back there and we look into all different models and we tested all the fundamental electrophysiology and basic biology of this channel, deposition, the physical density of the channels in a critical juncture in the neurons, what we see is like quite overwhelming preclinical efficacy. So when we had that before on SCN2A, on the different models with SCN8A on the allogenic model, I think the way we're looking into that is like those are very good translational models.

Now we have clinical data on those indications that translated well. So we expect to translate well as well. I think it would be a little bit too early to guide on how well the translation would be. But you've got to remember, from an overall DEE perspective, there is basically nothing for these patients as well. So while I'm incredibly excited about showing results maybe the same, maybe better than what we're seeing on 2A and 8A, it's absolutely not needed to deliver a very fundamental change on the way these patients are treated right now.

But as I said in the past, we're going to see this soon enough. So we're just going to keep our heads down executing on EMERALDs, and soon enough, we're going to be discussing hopefully, significant benefit for patients on that population.

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

Marcio, maybe a little bit of a follow-up on that last question in terms of relutrigine and then I have a follow-up on vormatrigine. But just sort of when you anticipate utilization, do you see sort of utility across the -- it sounds like you see utility across the entire spectrum and even in indications where there are sort of ASOs or sort of more targeted therapies being developed and arguably sort of relutrigine will sort of become a workhorse used regardless of what other therapies may also be deployed for a particular patient populations.

Yes. No, that's a very good question, Doug. The workhorse, probably I wouldn't use that term, but I'm glad you did because I think that's one way to look into a drug like in a toolbox like relutrigine, where physicians would have that available that they don't have right now, right? They have to ask too many questions, too many trials. Like unfortunately, a lot of those patients don't have that time to keep trying and optimizing. And quite importantly, like there's, what, 20, 25 drugs that are normally tried in this population, virtually none of them have been tried and officially, like with randomized studies properly developed in pediatric populations or in adolescents or early adults here. So we never talk about that other side of label use that we really don't know what you're doing on those populations. So what we hear a lot from physicians here globally is that certainty of the drug that's being rationally developed for this indication. So there's a lot of enthusiasm there.

Now to think that this is a silver bullet would be like completely absurd, right? There is not such a thing as a silver bullet in medicine. I think we all wish there was, but that isn't. So we do see this as a kind of an overall background therapy for some patients, ideally would be monotherapy. For other patients, they're going to continue in other drugs.

You mentioned ASOs, particularly. I think ASOs are getting consolidated as kind of the second workhorse I think we're finally beyond some of the dreams we had about other modalities on gene therapy and really understanding that, that's a very, very good mechanism. So combinations between ASOs, for example, and others and relutrigine, we expect to be the norm. We look forward for the moments where these discussions are about how the use is happening versus all these hypotheticals because these patients don't have a lot of time and really excited about helping them.

Okay. Great, Marcio. That's really helpful. And then just on vormatrigine, I'm just curious, in the RADIANT study, as patients go sort of past the initial point and we're in the open-label extension, I'm just curious, have you gotten data or seeing data of patients who are withdrawing some of their background meds, sort of a little bit of a preview or look, if you will, into the POWER3 study, and in particular, patients who are maybe able to pull off sort of some of the more problematic -- sort of efficacious but perhaps more sort of less tolerable drugs like cenobamate or carbamazepine, et cetera?

Yes. We're seeing across the board reduction, elimination, removal of background therapies as patients continue to have experience on the open label vormatrigine. Physicians are very excited about the possibility, and I would say patients are more excited about that. As you can imagine, of course, efficacy is king here, right? But the queen is safety for these patients. And it is very hard for them to daily operate as humans when they are like on all those medications. So it's always very important. It's not only that, right?

I think one of the drugs you just mentioned has just been like put on a new warning for drug-induced liver injury. So you got to think about the long-term impacts of these drugs and being vormatrigine at least so far, like so clean, it's quite important for these patients as well. So we're seeing more and more enthusiasm. Of course, every time you remove a drug, the first question you need to ask is what happens to the primary measure, what happens to seizures. And I'm very happy to preliminarily report they were seeing exactly what we were expecting to, it's maintenance of seizure control while really not being necessary to use.

I believe you asked this from a clinical perspective, but I'm going to jump into here into the commercial perspective as we believe the value proposition of by the very first time on a drug that you can sequentially reduce the use of other drugs is very different than a drug that is just from the top, get used for a little bit and may be removed. So very excited. I think we're going to have more data and more discussions to talk about that when we have the POWER1 results as well and giving an overall program update.

Our next question comes from the line of Francois Brisebois with LifeSci Capital.

Congrats on all the progress. It's quite a 2025 for you guys. So, maybe on elsunersen, there's a lot to touch on, but I don't think much has been touched on this one. Can you help us -- EMBRAVE data is coming soon. So just maybe set expectations there a little bit. And I think there's so much going on with the company that maybe help us understand why it's so important that the update on just having a single-arm comparison for EMBRAVE3 and what that means.

Yes. So, thanks for that, Francois. The -- so elsu, as we call like elsunersen slide, it definitely sometimes gets the backseat on this question. So I appreciate we see in a sense, right, linking your questions to the questions, this is like an ecosystem. All these drugs are all going to be used. They're going to be different case on use one more and the other less or combinations and you name it in the future.

So we have this cohort right now, nine patients, 3:1 randomized to sham or drug. Our intention there was to continue to understand the safety, the efficacy, the PK of this drug. But we're very excited because every time you have control data independently or even open-label data independently of the number of patients is yet another opportunity for us to understand the drug impact.

We know the study went really well with these patients like did really well from a safety perspective since that we can monitor like generally, which is not a given, right, in any given disease. And we believe that it can be quite informative. The FDA left the door open for us on the discussions we had about the overall value of the data set on the overall program, right? So we wanted to make sure we're very respectful and we're mindful of that, but it can have a very high value depending on the results here in the next few months.

Now when you look into the -- we're very pleased and slightly surprised that the agency was really pushing us to actually get EMBRAVE3 to be controlled on baseline. I think they're definitely putting their money where their mouth is in terms of accelerating drug development for drugs with a high potential translatability plausible mechanism and this drug fits right in all of that. We did switch the study globally to a single arm with the patients randomized -- well, I guess, not randomizing now they're dosing on the study. And it's been like great experience with all the PIs and all the patients globally.

So a little bit longer on the time lines, not really long on biotech years, but long for us since there's a lot going on. But we do expect to be done with the study this year as well, which would potentially get another -- yet another NDA in the near future.

Very different positioning, as you can imagine, commercially very complementary to the relutrigine efforts that we're doing same prescriber population, overall same patient population. So we can see how synergistic this can be on the overall life cycle of the company.

That's very helpful. And then on ulixacaltamide, I don't think you mentioned anything about ex U.S. efforts. I was just wondering, such a big market here. I assume ET is everywhere else. Any thoughts there that you can share? And then the launch, obviously, without priority review, this is maybe a little premature, but you've had so many trials and so many patients on this. I'm just wondering in terms of line of sight in terms of the launch trajectory off the bat, do we know where these patients are? Or any color there would be helpful.

Yes, yes, absolutely. So, maybe the easiest part of the question, you absolutely know where these patients are. I think we have daily motivation as patients keep calling our IR line, keep sending us messages and keep reminding us to keep pushing that they are waiting. It's quite motivating for me and for the rest of the team to keep moving there. And just like the millions of patients that we have mapped to prescribers in the U.S., that in a sense, I think it answers the second question or the first question that I'm answering second, while there is huge unmet need outside of the U.S., and we appreciate that, and we are very compassionate in relation to that, the focus of the company has to be in the U.S. right now.

We were laser-focused on making sure the highest possible quality NDA was submitted. Now we are laser-focused at the highest possible quality launch is done for this. And when looking into the magnitude of this launch, I think you would be conceived and intended for us to get distracted at this point in time with other geographies. So very good trajectory, very good number of patients, as you can imagine, in open-label extension right now, which we would expect they would transition right away to commercial. other pools of patients that we believe are going to be right before and then just the spontaneous demands that we are seeing piling up on top of our database already for the launch. So I don't want to get over our skis here, but it is definitely trending towards a successful launch.

Our next question comes from the line of Ami Fadia with Needham & Company.

Congratulations on the submissions, both the submissions this month. My question is on vormatrigine and regarding how -- what you assumed for your peak revenue potential, particularly regarding utilization in first line and if you could provide some color on how you see utilization in earlier lines of therapy impacting persistency of patients and duration of treatment? And how will the POWER program help you build the clinical data that supports or provide some color on how long patients stay on treatment as they get treated with vormatrigine in earlier lines of therapy?

No. Thanks, Ami. So the retention we are seeing right now, right, as an early indicator of what you are asking, it's incredibly high. And once we talk about POWER1 results, we're going to be able to talk about that as well. Patients not only participating in these studies, but really staying on the long run. So that gives us an early flavor of how retention in overall commercial is going to be. And of course, they are staying on drug differently from other drugs and different from other trials because they are having a benefit and because they're having a safe experience with this drug.

The way we currently forecast the movement between third line, second line, first line is actually very responsible, I would say. So we're not looking for this at day one of launch, we're not even looking to the year one at launch, we know it takes time for these things to happen. We know that the overall penetration is not like the highest. But when you look into our peak revenue right around $4 billion or so in overall, like you can imagine that we couldn't just be hyper penetrating the first line because otherwise, this would be much, much higher than what we have right now.

So there is a huge potential there for upside, as you can imagine. But at the same time, as we -- there are many firsts that happened for us, right, in the last few years. And I think we're always very responsible to say what we knew and what we didn't. And I think what we know right now is that there's incredible interest on utilizing this drug. What we don't know is the dynamic of that. So we are really keeping, I would say, very tempered our enthusiasm in terms of how the penetration is going to be there, and that's reflected on our conservative to realistic one could call PIC revenue right now.

Our next question comes from the line of Brian Skorney with Baird.

I guess we'll get some guidance on NDA acceptance, but wanted to just get your preliminary thoughts on if the review division has given any indication on an advisory committee for either relutrigine or ulixa. I mean it seems that ADCOMS are getting more rare under this current iteration of the FDA. And relutrigine's mechanism seems pretty straightforward with the data. I probably wouldn't require one, but thoughts on ulixa in particular.

Yes. No indication whatsoever at this point in time. One wouldn't expect much of an indication before day 60 and day 74 interactions with the agency, but there is no indication right now, Brian.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on all the progress. As you plan your prelaunch activities for both ulixa and relutrigine, can you talk about the potential synergies you can leverage between these two launches? And then eventually, how those synergies could help set up your future launches of vormatrigine and elsunersen?

Certainly. So from a -- I'll take from the borrowing side, right? From an infrastructure perspective, back-office perspective, lots of synergy and how things are set up, and we've been doing a lot of that on the backgrounds, like how the systems are set up and so on. Until not that far in the past, we were actually considering a lot more synergy in the field as well and on the approach to the market because we believe before EMBOLD's positive results last year that would have a little bit more time with relutrigine, so we'll be able to leverage that. And that changed a lot once we are now really launching two drugs in about the same time. While there is a very significant overlap in I'm going to call ZIP codes, right, like hospitals that have or clinics that have very high overlap of patients with ET and DEEs or focal, we don't believe that it's prudent right now to take any distraction. So we're taking a go-to-market strategy for both for individually for DEEs and individually for essential tremor to maximize each one of them.

Now since your question extrapolated to the future, Jay, when you look into like focal set seizures, for example, generalized seizures, you name it, other things that might come in the future. There's very, very high overlap between prescribers for the majority of the epilepsy patients today and the majority of the essential tremors today in the market. So you can see how a Praxis presence might be beneficial at that point in time.

Now we are talking maybe two or three years from now and that we're going to be maximizing that. Now let me bring back to like 60 days or so from now when we're going to be in Chicago with all these prescribers. If we were to count the universe of prescribers coming to the Annual Meeting of the Academy of Neurology, we're talking about over 70% of the prescriptions for ET and Focal in the U.S. are present at that meeting. So there is a natural overlap here. We're just going to be maximizing that overlap more a few years from now than a few months from now.

Our next question comes from the line of Kambiz Yazdi with BTIG.

Congrats on the NDA submissions. Three questions on my end. First, can you provide an update on the essential tremor patient database? How is that already validated the size of the ET market?

Second, the FDA's default position is that one adequate and well-controlled study combined with confirmatory evidence will serve as the basis of marketing authorization of novel products. How do you think about that with regards to vormatrigine and FOS?

And then my third and final question is, how should we think about the timing of relutrigine EMERALD top line? Would an interim analysis be a possibility for EMERALD?

Thanks, Kambiz. I try to go through your questions here if I understood them correctly, right? So on -- and I think I missed the very first one, so I might ask you to repeat which one was on ET.

Yes. The first one was, can you provide an update on your essential tremor patient database? How is that already validated in the size of the ET market?

Yes. So we'll continue to both validate and grow. And I think we intentionally didn't talk about this today since now we are moving from the clinical focus one to the commercial focus effort, and we're going to give like a larger update at our Commercial Day in the near future there. So I'm going to keep you holding your breath a little bit in relation to that.

I'm going to go to the EMERALD and then go back to the second question. So, of course, there's always an opportunity for In-Trem. It's not a current plan for EMERALDs. And the reason why it's not a current plan is really the pace of enrollment in EMERALD right now. I think we've been realistic/conservative about the time lines today, but that is really a very fast pace of enrollment that might not allow for that.

And then on the last one and how we think about generation effects vis-a-vis the Commissioner like New England Journal of Medicine yesterday publication, we applaud it. I think it can be and will be -- I have but trust on our country that's going to be used responsibly. And we believe that in drugs where very clearly like epilepsy, very clearly, the second study was not necessary in the best. Those are good case studies and tests for the future. We could not possibly be trying to guide you today that, that's going to be the standard for our drugs. There's a lot of water that needs to go under that bridge, but we are enthusiastic about what that can do for drug development and for Praxis, particularly in the near future. So stay tuned.

Our next question comes from the line of Justin Walsh with JonesTrading.

With your clinical successes, have you been seeing increased attention paid to your Cerebrum platform? And related to that, can you remind us how both Cerebrum and Solidus are differentiated in their ability to select quality candidates for your pipeline?

Yes, yes, absolutely. We do. As you can imagine, that is I think just in like a renaissance, maybe I would say, on understanding that the best mechanism to address a lot of this disease is through antisense oligonucleotides. So we're seeing a lot of interest across the board actually on this. You're going to hear more in the near future about how we're going to maximize. I also believe that there's a different way. We talked about standards today. I talked about plausible mechanism today. There are different things there to maximize.

We always follow two pillars, right, the biology, and what is the best way to address and then the business on the other side. Without business, biology is irrelevant. Without biology, business is irrelevant. So I think we try to do both of them, and that's why we're here today discussing the successes and the future success. So I think that is -- stay tuned, but there's going to be a lot more on that platform as well.

Our next question comes from the line of David Hoang with Deutsche Bank.

So maybe first one on ulixacaltamide in essential tremor. Could you just discuss a little bit about the distribution of the prescriber base? How well do you understand whether these prescribers will be based in, let's say, academic centers versus community, this is a product that would be prescribed by general neurologists broadly?

And then one on vormatrigine. As we think about the evolving landscape in focal epilepsy, there's several potassium channel focused therapies that are in late-stage development and potentially coming to market soon. How do you think vormatrigine fits in amongst those products? And what would docs look at when selecting a therapy?

Thanks, Dave. The distribution, and I would say the distribution of patients and the distribution of drug and the prescribing pattern is very well understood. I think we've been talking about that for a bit. It was one of the very first functions and knowledge that we built in the company. I would arrogantly tell you that we have an exquisite understanding on this. And each one of the physicians that have case in the U.S. right now is the majority of them, the vast majority, general neurologists, and they're very eager and willing to engage with us.

I think on pharma and the competitive landscape, this was not and never going to be a zero-sum game. We welcome. We are cheering for the next readouts on this space coming up soon. And we believe that, that is really -- is in the best interest of patients that there are multiple positive readouts and drugs, and we can use them. And we just see the path to first line only happens with vormatrigine. So competitively, welcome going to have some competition on the refractory patients on the third line, but there's no competition on the earlier lines. Thanks for your question.

Our next question comes from the line of Ben Burnett with Wells Fargo.

I want to come back to an earlier question on ulixacaltamide and just the potential to explore titrating patients. I think you mentioned an alternative titration protocol. I guess curious if you could give us a little more color on this. And I guess, would this alternative titration protocol start patients at a lower dose?

And then secondly, you also talked about standard review for ulixacaltamide, and I think you walked through a couple of sort of business reasons for that. But it feels like it also would give you some time to maybe iron out a titration protocol. And was that also a consideration?

Yes. Thanks, Ben. The -- no, there was not a consideration. Actually, I'll say there was not an important consideration. Of course, it's always up to the FDA if they want to discuss more. We had a very robust discussion about that topic with the agency before it was very good to see that this is not a major concern, but there's obviously an interest from us and from them when there is an efficacious drug that we try to actually expose and get the maximum amount of patients. That is the idea. It is not a lower dose, right, starting at 20 milligrams. It's just staying at 20 milligrams for longer because what we see here is what looks like it's really just a few days that they stay longer on that dose that tends to subside the side effects and then they have the opportunity to have the effect.

So that's the idea there. I think, of course, there's thousands of things that can come up in conversations with the agency, but that was not one of them that we are planning as a main conversation for sure.

I would now like to turn the call back over to Marcio De'Souza for closing remarks.

Yes. Thank you, everyone. I think we run a little bit even over the allotted time. So I appreciate you all hanging in with us here, the enthusiasm shared by all the analysts and our shareholders. I can't say how much I appreciate and all of us here at Praxis appreciate the patients that participate in all these studies that continue to engage with us as we are here very humbly submitting NDAs, which I don't believe has ever been done by a company in our stage on the same quarter. The real motivation for everyone that worked like days and nights on the last several years, but particularly in the last few months has been the fact that there is someone, as we say, outside of the door that we don't know they need these drugs.

So just going to dedicate this moment to all of them and thank them for participating in our studies. I looking forward to interact with all of you soon, and thanks for tuning in.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Okay. Good afternoon, everybody. Thank you for joining us. I'm Doug Tsao, Senior Analyst at H.C. Wainwright. We are thrilled today for what I think is a very unique event. We are joined by Professor Chuck McCullogh, who is a Professor of Biostatistics at UCSF and a real expert in the use of mixed models and really author of what I think many consider as the sort of definitive textbook on the subject. We are also joined by Marcio Souza, who I think most of you are familiar with, who is the CEO of Praxis. So we're focusing today on the Essential3 program. I think this is a little bit of an unconventional format.

The reason we're doing it this way is not only can we get the perspectives and insights from Chuck on some of the questions that have been coming up around Essential3, but also sort of accelerate the sort of cycle time for addressing questions by having Marcio here. So I also want to make it clear upfront that Chuck is not affiliated with Praxis in any way. He is an independent consultant. So my hope is, is that Chuck will provide some insights that will help everybody feel sort of better educated on the program and as well as ask some tough questions that Marcio can provide some insights.

So Chuck, I think as a starting point, I think it would be really helpful if you just provided sort of a 2-minute refresher on why you use an MMRM model and its value for this type of clinical study? And ultimately, do you think this was the right model for them to use. And then maybe if you just have an overall impression of the data as you've seen it.

Certainly. So I mean, this is longitudinal data. We collect data repeatedly over time on the same people. So from a statistical point of view, that's called correlated data because, of course, data within the same person is similar over time, more similar to their own data than to other people's data. So that requires a statistical modeling method that can accommodate this repeated measures correlated data. You also need to be able to have an analysis method that allows for flexible modeling. So for example, you want to adjust for baseline ADLs. In the models that Praxis used, they also adjusted for things like a family history of tremor. So you have to have a flexible modeling framework. So that basically boils you down to 2 choices.

There's mixed model repeated measures analyses, MMRMs and what are called generalized estimating equations, name is not so important. It's just another method for flexible modeling of correlated data. But a practical reality of any clinical study is there's going to be missing data, there's going to be dropout, and that needs to be accommodated. And so mixed models are well known to produce more reliable results with missing data compared to these generalized estimating equation approaches. And in this study, there was appreciable dropout leading to missing data. We didn't get to measure the activities of daily living for every person for every week. And so that gives a clear preference to mixed models in this context.

So if you had come to me completely independently and said, "Help me write a statistical analysis plan", this would almost certainly the path down which I would have led. So the start is using an analysis method that I would deem most appropriate. My general reaction is I start looking at the results, the results are highly statistically significant. If I back out p-values from the confidence intervals there, the p-values are really tiny, very strong statistical evidence. And so this should give robustness to any violations of assumptions in the analysis methods. So all that is good. There are some concerns that we'll talk about, I think, a little bit later that would have been concerns in my mind as well that need to be addressed by analysis of how robust these results are. But that's -- those are my sort of initial impressions.

Okay. And then, Marcio, with that as a backdrop, maybe just provide an overview of the Essential3 program and sort of the key considerations in the design following the Essential1 study results?

Yes. I think I'm going to try to build a little bit of what Chuck just mentioned, right? So from the very beginning of this program, from the very first interaction with the FDA we had, there was no real other choice of model, other choice of methods in the discussion, right? I think that if you go across the board and look into neurology in general, but even outside of neurology, longitudinal data is almost always analyzed using a mixed model. So that may be important because I think there was some questions about like when did this come to play. Even on the Phase II, the Phase IIb, that was always the case, right? But I believe, and correct me here, Doug, if that's not where your question is coming from, when you look into the actual hypothesis that was generated to design Essential3, right? So we didn't come up with Essential3 with the Phase III program like out of in there. There was a prior study, there was a previous study that generated the hypothesis here. There were a number of key elements there.

The first one was the population, right? So we always define a population first. It's like what are we studying this. And very similarly to what we're doing -- what we've done in Essential3, the idea was to use a population that was reasonably severe, right? When you look into the baseline for those patients, that was pretty high in terms of the severity and equally actually a little bit more severe arguably on Essential3, but very similar. So that was important. They were not really treating people without like significant impact on their daily living. The second part that was incredibly important is -- the FDA, actually, they were ahead of us on that in a sense, they insisted that we use the ADL modified in a way that they requested, right? That's why we call it mADL, it's the modification on the scoring after the data is assessed, and that was a request by the agency.

Actually, when you talk to physicians, they normally quote the ADL because that's what they assess, but the actual measure is slightly smaller numerically and therefore, harder to reach statistically like significant results, as we said before. With that knowledge in mind, the program was created. You got to remember as well that when you go back to Essential1, the result on the mADL, while it was not the primary at that point in time, it was positive was actually the p-value was lower than the 5% threshold that had been defined for that as well. And based on that, the Essential3 program was created. Now we knew at that point in time, we needed more patients to actually get the certainty to be higher. But that's how the study was created in general. So it's been very consistent, if I may, throughout the program.

Well, and I guess just really quickly, just the overall structure of Essential1 because there were 2 studies, right, Study 1, the parallel design as well as Study 2. On Study 1, you did have -- you changed the primary endpoint in the study midway through. Maybe just talk through quickly the process what led you to do that? That was a decision you made after the interim analysis, but you didn't sort of make the change until September. So kind of what took so long?

Sure, sure. So I'm glad you asked those questions in sequence, right? Because if you look into back to Essential1, that was an 8-week study. When we conducted -- the IDMC conducted the interim analysis and we decided to continue the study, we had to, I'm going to say, slow down, slow down by asking the questions like everything we know about the program, how do we know the drug to be effective at how fast and all these questions. And for how long do we have certainty on the estimations for the projection of the primary endpoint, right? Like reasonable, I believe, questions to be asked. And there was one thing we knew that 8 weeks was how we base the study, so day 56, number one. But there was something that was quite important as well when you talk about the design of Essential3.

We made the decision, one could argue a very high bar decision, a very complex one to randomize patients to Study 1 to the parallel group or to Study 2 to the stable responder randomized withdrawal. That is incredibly difficult to do, number one. And a lot of people don't do it because you increase the -- like the bar in terms of enrolling 2 studies at the same time. One of the things that came from that decision was that the studies were identical for the first 8 weeks, identical in every possible way, the patient pool because they're randomized based on the same stratification factors that Chuck's just mentioned that we had as well as covariance for the baseline. We -- or the assessment, they were blinded to study personnel, to patients, all the way.

And that equality, if I may, ended at week 8. And then after week 8, the responders on Study 2 got randomized to stay on drug or placebo. So we changed the assessment after that. So in order for us to actually even further refine the estimation, we went back and said, where does that end at week 8. And it took a while, of course, one would always like go back, this is a high stakes decision. We should not take in a rush. We like took our time to like think about that to simulate and so on. And it takes time to think. It takes time to simulate and takes time to write the changes and to submit to the agency. That's why we've done this way. In the grand scheme of things, I don't actually believe that's a lot of time.

And Marcio, just to confirm, right, you did submit that ahead of locking the database for the study.

Absolutely. There will not be a valid change if we had not done this without knowledge, right? So that was no knowledge of the allocation on the study or the group level, the individual level, any of that before the change were memorialized, number one. Implemented because we implemented the change. We amended the protocol, amended the SAP, we submitted to the IND, we sent a letter to the agents, so on and so forth. So everything was done way before the database was actually locked.

And I think Marcio, it's important to remember that sort of changing the midpoint or the endpoint mid-study is not without significant precedent, right? I mean we even saw it recently with donanemab's application where, in fact, you actually had the agency disagree that ultimately was not deemed sort of a consequential to the assessment of efficacy. And then I want to come back to Chuck in a second, but Marcio, I know you've sort of provided a lot of detail and you said that it was actually highly significant. What was the actual p-value for at day 56 on the primary endpoint?

Yes. I think that is the reason why we didn't show this before, I'll tell you right now, but it gets to a point there was like why are we even going there, right? Like I described this before as silly, right? There are certain things that we do that they get silly. But the actual p-value was to the order of the 10 of minus 6. So if you think about that was after the dots there, the point was like five 0s and then the first positive integer, I think it's hard to believe that anyone would consider that even close on the payer tests. But again, I should ask Chuck, what he thinks.

And Marcio, you have said that you were positive on the original endpoint, right? As much as you had made the change, ultimately, in some ways, there was much to do about nothing. I mean, can you care to provide some color on how successful it was on that endpoint as well?

Yes. So it's worth to say that was not only at the original endpoints, right? There was the day 84 assessed as the average contrast between day 77 and 84, and that was to the 10 of minus 3, so like the p-value. But it was at every time point, each one of the time points assessed, including day 14, right? So day 14, day 28, day 49, 56 like 63, 77 and 84, all of them were significant. And I think it matters, right? We're basically saying at no point in time, there was like a weird fluctuation here that you lost significant -- that would be a problem. We've seen that in several trials before that there is some fluctuation that did not impair their ability to get approved. But I think in this case, it's quite important as well to mention that.

And Chuck, when you hear those degrees of sort of statistical significance, I'm curious, does that -- how does that influence your sort of initial assessment?

Yes. So let me back up just a second. So whenever there's sort of last-minute changes in an analysis plan, especially the primary outcome, it sort of sends up signals to me that I better pay attention, I better scrutinize this a little more carefully. And so the same considerations that you brought up come to my mind. Was this decision made before database lock? Yes. And so that's important because things haven't been unblinded yet. And so you don't have -- you're not making these decisions based on what you know the results are going to be. So that's number one. I'm less swayed by the necessity of having equal time periods in the 2 arms of the overarching studies. You've got the data for both. You can analyze them using only the consistent data if you want to. It's a question of what you declare to be the primary endpoint. Okay. So it's been changed. Okay. So stepping back, in the bigger scheme of things, this is a pretty minor change. It's not like you change from one metric to another metric. All you did was you shifted the time at which the primary assessment was going to be declared.

I've seen people in clinicaltrials.gov just say, the primary outcome is mADL, they don't even specify the time in clinicaltrials.gov. So it's a relatively minor change. Okay. So still, okay, there's a little suspicion here. There was a last-minute change in the primary outcome. So now I turn to the sort of issues that Marcio was talking about. Okay. So in kind of worst-case scenario, let's imagine a conceptual trial where you declared those endpoints, 84 and 56 to be co-primary. What would you have done? A relatively draconian adjustment would be to do a Bonferroni adjustment. That means instead of testing at 0.05, you test at 0.025. That lets you look at both endpoints. and take either one that's statistically significant and declare success. Well, these p-values are tiny, as Marcio was saying. And again, I back calculated them from the confidence intervals that are public information. And they're very, very small. So that still leaves me pretty convinced because even if I say, okay, I'm going to adjust for co-primary outcomes, I've still got statistically significant results.

And Chuck, that's really helpful. And I think one of the things that you talked about, right, when you talked about the value of an MMR, there is missing data. And that has become a focal point for investors and sort of thinking about sort of the various sensitivity analyses that the company has presented. Can you just give us sort of a brief tutorial on missing data and how an MMRM model handles it and help us understand what sort of missing at random and missing not at random actually means.

Sure. And again, I think we're transitioning to a different topic because I do see these as sort of separate issues, the choice of the primary outcome versus how you deal with missing data. So let me talk a little bit about mixed models and missing data. So as I said earlier, mixed models are clearly preferred in situations where there's missing data. And it's almost always the case in any clinical study, there is some. And so that's often the reason that people are guided to use these. Why is it that people like them? It's because analysis of data using a mixed model approach without any formal consideration of missing data. So just sort of pretending that, okay, the data is unbalanced, but there's no real bias to why we had missing data for some people under certain circumstances still gives valid results.

So that's the key reason people like that. Okay. What are the certain assumptions? These assumptions are technically known as missing at random. Now that's a terrible term, and I wish that whoever made that term popular would be strung up because if you try and parse it as an English language, it leads you to the wrong conclusion. I prefer to think of it as missing that's predictable from the observed data. In this case, that would include anything in the model like family history of tremors as well as any previously recorded value of ADL on that person.

And so that then extends the protection fairly widely. Missing not at random, that's the more problematic case because the mixed models don't necessarily protect you there, means the missingness is dependent upon other things like the value of ADL if we got to see it, which, of course, we didn't. When the data are missing not at random, then a mixed model analysis can give you results that deviate systematically from an analysis that you would get if you suddenly magically had access to all the missing data. And so then that's the legitimate concern. Again, it's not just a concern in this particular study. That's a concern with any study that has missing data, which again is virtually any clinical longitudinal study.

And I want to clarify because I think this has been sort of a misconception amongst some is that a patient dropping out because they're doing poorly on an observed basis is not a violation of MAR, right, missing at random as well as an imbalance and discontinuation between active and placebo is also not automatically a violation of MAR.

Right. So when people are dropping out because you've seen this -- look now, say, a patient is not getting better and they decide to drop out of the study, that's predictable from their pattern of ADL measurements up until that point. And so that could well be missing at random. And you're right, the mere fact that the discontinuation rates or dropout rates are different between the arms is not necessarily an indication that the missing at random assumption is violated. I'm a senior statistician for a recently completed randomized trial treating depression. And one of the arms was an antidepressant drug. Our endpoint was declared to be depression after the end of treatment, but we had, of course, intermediate measures of depression and people taking these pills got immediately better and discontinued. But that was completely predictable from these early measurements of depression. So again, that led to a big difference in discontinuation rates even though the MAR, missing at random assumptions are still quite plausible.

And is it fair to say that with the model of the Praxis used assumes more, but we do or should consider the possibility that the mechanism of missingness is missing not at random, and we need to stress test the data for that possibility as well?

Yes. I'm not so sure I'd say it assumes that. But again, I'd go back to under missing at random assumptions, it still gives valid results. and is not guaranteed to give the results when it's missing not at random. And it's an unfortunate fact, maybe not too surprising, but you can't tell if data process is missing at random or missing not at random, by looking at the data because it depends on things you didn't get to see and assumptions about things you didn't get to see. So it's almost always a good idea to stress test these missing data assumptions by doing sensitivity analyses.

And what would be sort of the way that you do sort of assess the plausibility of MAR and what are some of the questions that we should be thinking about here?

Yes. So I go through this process and try and think about it in a sort of twofold. First, is the situation. Unfortunately, this is -- because it depends on unknowable things from the data. It depends strongly on the clinical context and what you know about what's likely to cause missing data. So first, I try and think through is the scenario likely to generate data that's missing at random? Or is it likely to generate missing not at random. I mean just to give an example, so in a recent study that had completed, we were -- we had a scale we were using. It was not validated nor proven to be useful in the population we were studying until the study had already started. So the first few people, the first 100 people out of many hundreds we recruited, we were not able to use this scale because it had not yet been validated. But after the first 100, we decided it was the better scale.

We made the hard decision to replace the one we were using. So we now introduced missing data for the first 100 people recruited into this trial. So you know from the context that there's a strong argument that that's missing at random because the fact that it was missing was just related to the fact we recruited them earlier. I mean you can imagine things that it's missing not at random, but they're pretty implausible. So there, the situation gives you sort of confidence that it's missing at random. On the other hand, and probably more relevant to today's discussion, when dropout is related to adverse events and causes discontinuation in the active comparator arm, then we have more suspicion that things are likely to be missing not at random. And that's where it's even more important to stress test by doing sensitivity analysis.

And when you -- Marcio, sort of how do you think about it? How did you go about addressing these issues?

Yes, absolutely. So the first thing is like what we hypothesized before, right? So the question is always -- should be always first is what is the primary model and then we talked about that already. And then how do we stress test the model, right? Like what do you -- if you consider things that might not be a random that are missing a random, how do you stress test? So the prespecified sensitivity analysis, which, by the way, was the same one on Essential1, the previous study was the one in every statistical analysis plan here, and it's actually a commonly used one for MMRMs is the tipping point. The principle there that there is a point by which you keep removing benefits or adding a penalty, whatever you want to think about it, that would tip, right, would become nonsignificant. And the second judgment you have to make there is like what is clinically plausible because you can't interpret just a mathematical change. You have to interpret that as clinically plausible as well.

And when you put the 2 together, the proposed and the memorialized one on the statistical analysis plan was a tipping point analysis starting at 0.5 a point as penalty and going to 2.5 points. So that was the maximum on the actual analysis plan. The subsequent to that, and as you know, it did not tip like not even close to actually becoming nonsignificant at that point actually much larger than that, if you care to know, is much, much larger than 2.5 points, which is already pretty absurd because the patients don't get worse and so on this case. But then the other question that we asked ourselves, and you've seen this in our disclosures is like for these patients that we didn't have information, I think Chuck just talked about it, we can only hypothesize things. But you can ask what could be a reasonable replacement for their values, right? That's what all we are doing here is replacing the things we don't know. And we said, okay, placebo would be a reasonable replacement for that. A reference, right, would be reasonable. And we've done a different method.

That was very clearly not prespecified. It's very common to be done, but it was not. The only prespecified was the tipping point. We checked the box already. But we've done that. And we tested, although the methods are very similar when you complete data, we tested using the MMRM feeding again the MMRM now the data is no longer missing, right? So you just fit the model there. And [ Onconova ] well was in very similar terms. And while we're seeing that once again, one could actually expect that is highly significant results on those sensitivities. So you're stress testing the model. We're not necessarily -- you made the example of Donanemab. So I'm going to bring that back because I actually think it's quite important since Chuck was mentioning about recent studies as well, right? That is relatively recent. As you know, there was not only a change on endpoint, but the agents actually comment quite eloquently that it doesn't really matter because the other endpoint was actually positive as well, kind of similar to the change in time points for us.

But quite interestingly, they actually requested a tipping point analysis. The agent said -- asked Eli Lilly, which they sponsor here to conduct and actually tipped at the first level. That did not preclude at all. the first level is very low, by the way, precluded at all the approval of the drug was just stress testing, I'm going to call it stress testing, how reliable to stress the endpoint was. It happens to be that on that study, it was pretty high the discontinuation rate as well. So it's not unequal to the situation we're dealing. So it's not only that there is plenty of regulatory precedents, number one, very recent as well, same personnel in the division for that matter. We're also tested with other methods, and those methods also result into very robust results at the end.

And Chuck, we did get a question from somebody watching who did want to clarify or just -- but you alluded to it that if you do have discontinuations because of adverse events, how does that impact our assumption of MAR?

Yes. So when you have discontinuation due to adverse events that you think are treatment related, so people are discontinuing the drug. It's unrealistic to expect that they're going to follow, let's say, we have a couple of values of ADL for them already and then they have an adverse event and they discontinue. It's probably unreasonable to assume that they're going to follow the trajectory that they were on while they were on drug and then they suddenly discontinued. So this is the place for what Marcio was talking about where you'd either say there are a couple of widely accepted methods for doing these MNAR, missing not a random analyses, one of which is tipping point and the other is return to reference where you say, well, I think they're going to switch to some other profile and a reasonable profile might say, okay, I think they're going to switch to look like a placebo patient that otherwise had sort of similar characteristics to this person who started in the active comparator arm. So that's a situation where I do think stress testing is more indicated and a missing not a random mechanism is more likely. Again, we can never know for certain, but the clinical context here would suggest it.

And so -- but based on what you've heard so far in your assessment of the data, do you think MAR is still plausible?

Well, it depends on which type of patients we're talking about. If we're talking about somebody who's got quite a few measurements of ADL, leading up to the primary endpoint of 56 days and is still on drug, probably quite plausible. If we're talking about somebody who dropped out very early, we have no follow-up measurements or somebody who discontinued drug, I think, less likely.

And Marcio, I think you sort of referenced it, and you did talk about the tipping point analysis that you conducted. Maybe, Chuck, it might be helpful for you to just sort of walk through how a tipping point analysis works. And Marcio said that I think it was -- they got to 2.5 standard deviation, 2.5 points. What is your initial impression of that, right? And I think that the p-value at half standard deviation was 0.026. Correct me if I'm wrong, Marcio.

No, you're right.

Yes. So okay. So let me back up and talk a little bit about how a tipping point analysis works. So again, this is in the context of data that's missing, not at random. So we have to make certain assumptions about how much, in this case, worse an active comparator patient would do when the data are missing. So we're basically saying, okay, usually, you start from, okay, here's what we'd expect their trajectory to be ordinarily. But now that they have generated missing data, we're not -- we're going to take that expected trajectory and make it worse by some amount. So typically, these are called like a delta adjustment. So we make a little drop. So we say, okay, maybe we expected that patient to have improved by 3 points on the ADL scale. Now we're going to decrement their improvement.

They're not -- they didn't improve by 3 points. If we have a delta of 1, we are going to say, okay, we're going to just make them say they only had an improvement of 2. So that would be like a delta of 1. And so we apply this value of delta, and we check to see whether or not it overturns the results, typically asking, are the results still statistically significant after I've employed this little delta. And so -- and then typically, you march and you increase the delta. Now I would nitpick with Marcio's approach. I mean a tipping point analysis should keep going until you tip it over and no longer get statistical significant results. They stopped at about 0.5 standard deviation. I'll come back and talk about that in just a second.

So that's how the tipping point analysis works. And in their case, they went up to 0.5 standard deviation, still had statistically significant results. So basically, they hadn't yet reached the tipping point for this analysis. There's been some questions about is 0.5 standard deviation too much, too little. Well, 0.5 standard deviation is a moderate-sized effect, a 2.5 point change on the scale is right around what a clinically important difference is. So even though, again, I would nitpick and said they should have gone farther until they actually tipped the analysis to be not statistically significant. They did go up to a pretty big effect size and did not see a tipping of the analysis towards not statistically significant.

And Marcio, a couple of questions. But first, I want to -- somebody pointed out, I misspoke. I think I dropped to 0 your...

You did drop to 0, I was going to correct you.

Yes, you were 2.5 [indiscernible].

There is an extra 0 there, but that's the start of this program, having an [indiscernible].

Too many 0s. How did you settle 2.5 points as half a standard deviation? What was sort of the rationale or identification of that? I mean you haven't necessarily talked or fully disclosed all the standard deviations on the primary endpoint. I think we had the baseline at 2.4, but just what was that? And at what point to sort of Chuck's question, I think that's a good one. At what point did you lose significance?

Yes. So number one, I agree, right? It's like if you were to reasonably hypothesize that you're going to keep growing, like remember, you control studies. I know we are going for this MAR and MR and scrutinizing the other endpoints. When you control the study at the 5% alpha level. And in a sense, deliver an eye on that, right? That's how we declare the study success or not. I think all we are saying right now is in a sense, gravy, the way I look into it. Should we have, in our craziest dream, imagine we'll go beyond 2.5 points of penalty on the sensitivity. No. Did the FDA comment when we submitted 2.5 as the maximum. No, they did not criticize that either.

Now in retrospect would I have prespecified keep going. Yes, absolutely. Like there's nothing wrong with that, right? We're talking about like a 0.006 value at 2.5% of course, the number is much bigger. And I would kind of leave a sense with that is like we normally would say you have to cross the 5%. We're in the 0.26% like you've got to imagine that the number is significantly bigger there. Do we need to be bigger is the question? And the answer is no, are we bigger? And the answer is yes. Are we bigger by a lot? Yes. And that should kind of close a chapter, right? Because this is a sensitivity, it's not even the primary.

I think if the primary was 0.0026, we would be like happy. And we're talking about a sensitivity with penalty here. So I talk about silliness. This is one of those things that got a little silly.

And Chuck, maybe you could comment just from your perspective, when you look at a study like this and how standard and half standard deviation, penalty is for tipping analysis, right? How robust is that? Or would you have said, gee, maybe it should have been 0.75 standard deviation or a full standard deviation. I mean I think to Marcio's point, like they came up with a number, and they could clearly go past it. So -- but to people who are saying, "Oh, gee, why didn't they go further?" From standard practice or from your perspective, how robust is half of standard deviation?

Yes. So again, to be nitpicky, I would have preferred to see a formal dipping analysis where you keep going until you tip. And then you have the thing in hand, you say, "Look, I didn't tip until one whole standard deviation, something. And that's completely implausible. I mean that's how these sensitivity analyses work. But that said, half of standard deviation is pretty well accepted as a moderate effect size. So you're saying that you're going to decrement the active comparator arm by a moderate-sized effect. And again, I'm also convinced by the very small P-value there because I know that just as Marcio said, that means you can go further and not flip it over. So again, I feel like I'm more nitpicking than strong concerns. And no, yes, I looked at it and I said, "Well, why didn't they keep going? They said, well, okay, the P-value is 0.026 and standard deviation is a moderate effect size. And so I'm not overly concerned with this.

One could jump there, right? And kind of, again, giving the -- as we are in active discussions with the FDA, I'm going to be a little bit careful as well. But is -- does it tip at 3? No. Does it tip at 3.5? No. Does it tip at 4. No. And then at one point, it gets to the point that I said it's silly, right? Because now we're penalizing the entire like study by an amount that is not reasonable on a highly heterogeneous patient population on 1 that you know placebo does not do much. You've got to put the clinical context on this statistic analysis as well.

Right. And to Marcio, to your point, when you're -- if it's holding at 4 points, you're taking patients to well below even the placebo response at that level, right?

Now we are damaging them. And like is that reasonable to actually say that. And I think that that's where it becomes unreasonable.

And Marcio, the analyses have all been on the MITT population. And to be in that, you needed to have a post-baseline assessment. Now I know you had the FDA agreement and alignment that this was the primary analysis population. We have gotten questions in terms of the ITT population as well. And so can you provide some perspective on sort of how that impacted your analysis?

Yes. No, absolutely. I would maybe separate without things here, right? So one is what the ITT would do to the actual results. That is nothing because there is no post baseline term. So the MMRM will just drop that. But that is not probably where your question is coming from. Your question is like what happened to these patients that are not available. And I think that that's where using the jump to reference here is important, right? Like you're saying, okay, for those patients as well, not only the other ones, we're going to replace their value. We're going to treat tens if they're not responders. We know it's not the case, right? We know that a very large proportion of patients respond. So we're actually penalizing quite like aggressively, and we show that data for the juncture reference. But I'm going to throw another one here because since this is a relative call. We did do another sensitivity analysis that is not in our deck that we completely replace their numbers by a 0 change.

So like basically a baseline carried forward, right, or saying there is no chance, like these patients are straight line because placebo arguably has small chains in the direction of effects. And that is also positive. So if there is any concern about what sensitivity does to the primary, that shouldn't be. Because the -- again, when you're talking about a 10 to minus 6 primarily when you're talking about every time point being positive, it is just very, very hard to actually negate the node by just going through this different imputations as we may.

Chuck, how do you think about the reasonableness, if you will, of considering patients that dropped out before day 14 as missing at random since we don't have sort of an observed outcome for these patients.

Yes. So as I said before, unfortunately, we can never know for certain whether things are missing at random or missing rather just from the observed data. We sometimes get clues. Again, as I was talking about earlier, if we've got a sequence of values and then we know that a person had an adverse event and discontinued drug, we've got sort of clinical expectation that they're going to change somehow. But these are patients for whom we have virtually no information, not even clues as to what we should be assuming.

So again, this is a situation where if you wanted to go to an ITT, again, the primary is modified intention to treat. So I wouldn't -- I don't get too concerned when there's an accepted modified intention to treat is the preplanned analysis. I always good to think about intention to treat. But this is a situation where, yes, you would definitely want to be doing some stress testing and by using one of the methods of assessing sensitivity to missing not a random data just to see what happens.

And Marcio referenced jump to reference and that being sort of one of the analyses that they did. Chuck, maybe provide sort of a quick refresher or sort of tutorial, if you will, and how that works and how that adds to the robustness of our picture?

Yes. So it's another well-accepted method of trying out a missing not a random mechanism. Again, it's a one that corresponds in many situations to be clinically appropriate. It's just saying that if I've got a drug, and I think that as soon as somebody discontinues it, they will look like a placebo patient and I'm going to choose the placebo pattern of data as my reference group. I'm assuming that a person immediately goes to look like a control patient. I'm assuming that's the reference group that was used in this situation. And so that's a pretty conservative approach by saying, I'm assuming that instantaneously from the beginning, this person looked exactly like a placebo patient. So you're immediately diluting the active comparator effect about as much as possible by assuming it looks exactly like a placebo.

And Marcio, your question that came in that I think might be helpful is just how do you think secondary endpoints sort of help us inform us in our overall population? And then I'd be curious to hear Chuck's preventive on that as well.

Yes. So maybe first on the statistic, how they are treated, right? So the primary had to be positive and then the secondaries were sequentially tested. I think it's incredibly important. I'm glad you asked that, right? There are a number of things we assess here as the secondaries and they're all positive and they're all very small P-values. One thing we haven't said publicly before, they're also positive at every single time point, right? And when you consider the way we structure the secondary endpoints, right? Like the first one is a clinical outcome assessments, the primary. So the MADL, the clinician assess the patients, then we ask what happens on the overall effects? What happens on the entire trajectory of these patients, not only at one time point, but on the entire trajectory. That is to the order of like 10 to the minus 7, the P-value, right? So overall, in the study, they're doing really well.

Then we ask the question like how patients see from the beginning of the study, they are health improving like using the PGI, how the clinicians see, how the clinician see the severity of the chains. For all those things, if you look across the studies in general, they don't tend to be positive. They don't tend to be positive throughout on studies that are not really giving a benefit because they are not assessing the same thing, right? So we consider, like, yes, we've been talking about sensitivity to the primary, but then go and ask the question, what happens to the overall health of these patients, and it's incredibly strong as well each one of those. So I personally think it's always very good to see secondary end points supporting the overall effect of the drug and not being conflicting, right? Because sometimes we see conflicting secondary endpoints in other studies. That was not the case here at all. They're all showing benefits.

And Chuck, I guess the question to you, how do you sort of look at secondary endpoints sort of influencing your overall assessment of the data?

Yes. So I often work outside the nonregulatory environment and it's especially important there. But even in the regulatory environment, I don't really have much to add over Marcio. I mean I do exactly the same thing. I look at the secondary outcomes, especially ones that I expect to be highly correlated with the primary outcome. And I start seeing it as a red flag when they disagree, especially if they go in the wrong direction, which I sometimes even happen. And again, so when everything lines up, pack sizes are in the right direction, especially when everything is statistically significant. I think that is pretty strong support for the primary analysis.

And Marcio, I guess, you did reference right jump to reference as having sort of being successful and obviously, a fairly at a robust level. I mean, how much further past placebo were you able to take patients before the model breaks?

Yes. Well, and you can go back and already said like you can replace their chains for 0 on the ones that just continue before day 14, right? Meaning you replace completely -- you remove the effect by on that case, 1.7 points in average because that's what placebo was and it's still highly significant. So you can make patients worse than they were at baseline. And it still be significant on the missing data perspective. I think someone would have to be institutionalized if they think this drug makes patients worse. And so therefore, like that should be a chapter that is closed, right, in terms of like how robust the primary is on this analysis.

Okay. And Marcio, I think I just want to before we hit -- we talk about sort of some of the integrated data. I thought it might be helpful to just sort of do a quick summary of kind of where -- what we've covered so far today. So I'm actually been working during the call to sort of pull together a little bit of a matrix. So if you give me a second.

Okay. I don't like surprise, but go for it.

And so just as we go through, I thought we were just hit the primary endpoint, as you talked about, Marcio, was sort of significant. When we did the sort of all-time points MMRM analysis, we're still significant. DGI, CGI, secondary endpoints, as observed, you just noted significant. You going to a sensitivity analysis using missing not at random with an imputation of greater than 2.5, we're still okay. Jump to reference placebo, we're still okay. I think you referenced maybe an ANCOVA jumped to placebo, we're still okay as well as going back earlier to the day 77, 84 right, MMRM sort of initial analysis, we are still there. So just sort of sticking to that. Chuck, I guess when you look at this and we'll -- we don't hold it up for another second. But I guess, Chuck, when you are coming back to just the main thing, when you look at that matrix, what is your response to perspective when you think about sort of a program that has that body of work.

Yes. So again, I kind of distinguish the 2 issues. One is choice of the primary end point. which, again, I find to be relatively minor, and the strength of evidence is there, again, even if I go co-primary endpoints. And then the key to dealing with missing data is doing lots of reasonable sensitivity analyses. So again, I'm pleased that there's multiple ways in which the sensitivity analyses were approached for missing data.

And then I want to sort of turn to -- we're sort of getting close to the hour, and I want to cover the integrated analysis, and we've gotten some questions from the audience, as you can imagine. But Marcio, we have some sort of alternative hypotheses, and sort of additional integrated effectiveness, I think hypothesis 3 as well as 4. Maybe just quickly provide some perspectives on how that you think will sort of inform the agency's view? And Chuck, maybe you could provide some perspectives on how you look at these types of analyses.

Yes. So the -- I'm going to start with the -- I never do this, but I'm going to start with the problem with comparing things like this, right? And normally, what we hear is there was no control on the second study. They're not done concomitantly. They didn't use the same covariant, blah, blah, blah. It's not the case here, right? So these two studies were literally stratified on the same parameters. And we -- from the beginning, we wanted to ask a question that how consistent is the arm on Study 2 to the one on Study 1. Since they were -- patients were unaware, right? They couldn't know which study they were at. And of course, we're not looking for exactly the same because by definition, like they wouldn't exactly the same is not something we see, but it's incredibly consistent, incredibly consistent. You saw the integrated analysis. What I can tell you is -- what is super interesting in this study is placebo on Essential1 and placebo on Essential3 are very, very similar, number one, and drug on the first arm of Study 1 for Essential3 and on the run-in period for Study 2 are incredibly consistent.

But then we ask a slightly different question was actually another brilliant statistician that suggested, I wish I could take credit for that, it's like, why don't you formally compare placebo and Study 1 to drug on Study 2 since they were unaware right? And that's one of the hypothesis for. And all of that is significant. Of course, when everything is significant when you put them together, they get even more significant. We're talking about a small p-value. That p-value is insanely small, right? But the consistency of the effect, I think it's important, number one, as we're making decisions on putting patients on drug clinically. But secondly, you see again and again in FDA reviews how they talk about consistent of effect being important, but love to hear Chuck's perspective on that.

I think you're right. When -- any time you look at sort of different ways to address the same question, and you see results that are not similar that sends up alarm bells. So yes, again, and of course, you're right that if you're finding statistically significant results with each individual comparison when you combine them, and the results are consistent in estimated size, it's just going to get more statistically significant. I'm much more suspicious when it looks like people are rescuing a bunch of nonstatistically significant results by combining. That's when Red Flag start going up in my mind.

And so what you would mean by that is when by sort of expanding or sort of by adding the populations you sort of start to overpower your analysis for arguably a non-clinically meaningful effect?

No, no. I mean, I did this 1 study, and I got a P-value of 0.06 and it didn't quite meet the threshold and I got a similar size effect in this other part of our overarching program, and it had a p-value of 0.08. So because they're consistent, I'm going to put them together and then magically, I get a p-value of 0.03.

Not at all, right? What happened here is like you have positive studies. Of course, you put it together, just trying to be intellectually honest. And when you get a p-value to be 10 of minus 12. Of course, if everything is positive and you continue to put them together, they're going to get smaller and smaller, like that is just logic in general, but we do get very, very consistent, which tells me the true benefit is being assessed on individual studies and on the combined study, and that's important. That's the #1 reason why you have to submit an integrated summary of efficacy to the FDA on an NDA to assess whether or not they are similar and here we are, in a sense, in a controlled way, getting that effect.

And Chuck, a question from the audience was sort of coming back to the question of dropout, right, especially due to AEs and when you have an imbalance, which we saw in this study, does it ever reach a point where it makes sort of you lose trust in the sensitivity analysis or tipping point analysis even?

So I think the -- it's not that I lose faith at a certain missing data rate. The way that I think about it is it puts more emphasis on how appropriate you think the modeling of the missing at a random is. So again, that's why you have to go to pretty high extremes in order to really stress test the system because the results then are very much model dependent, dependent on the model you're hypothesizing for the missing at a random data. So that's why I think it's important to do things like assume that the drug has no benefit or maybe even push it as far as a slight detriment just to make sure that things still hold.

So to your point, that's where things like the jump to reference analysis becomes more important.

Right and pushing the tipping point all the way out. So again, it's at some ridiculous level that it requires to tip it over, then you feel much more confident that even if some of the assumptions in your modeling weren't quite correct, you're still getting very strong and convincing results.

Chuck, one thing that I meant to ask, so I'm going to ask , and I think that some people sort of looking at this have struggled with is the fact that the company had a futility analysis back in March. And they've had difficulty sort of wrapping their heads around that we would have a futility analysis in March, yet when it comes time to finally continuing with reading out the full study, not only do we have a positive study, but we have one that is overwhelmingly statistically significant. And so maybe just walk through from your perspective, does that raise red flags for you in any way? Or just what is the real possibilities or probabilities that, that would actually occur?

Yes. So yes, the things that would cause me to sort of scrutinize a study like this more carefully where, as we've already talked about, change in outcome, relatively high rates of missing data and sort of more of a curiosity, a futility analysis that suggested that there might be a reason to stop the study. So I don't know the details of how the futility analysis was conducted. But typically, you project ahead and you ask what's the probability of a positive i.e. statistically significant result once I've concluded with all the data collection.

There are certain assumptions that have to go into that model. And if the data that's collected in the interim analysis is out at the halfway point, and then you've got another full half of the data to collect. If it's more optimistic than the data that you use to project ahead, of course, that projected probability of futility, not finding a statistically significant result can be off. And the proof is in the pudding in my mind. We don't need to go back and say what was the probability back then, given that we have convincing results now.

I've seen things like this happen in the past, things that only happen 5% or 10% of the time happen 5% or 10% of the time. And so yes, it can happen.

And is there any way that the sort of futility analysis could have informed the company's decision to change the endpoint? And does that sort of raise questions for you?

Right. So again, I turn back to the issue that it's a multiple testing issue. So what were the options at the time. So you did a futility analysis. And if I put myself in Marcio's place, it's like, what could I do that's legit that I can help to make this study be successful in the end. And changing little things like tiny tweaks on the analysis strategy, probably not going to make much of a difference. But for example, if I thought that the drug was going to have a much more immediate impact early on that might suggest I should move the time point earlier.

Okay. So now if I'm going to critique this, I'm in the multiple testing arena, okay, what's the possible benefit that might be gained by the company? Again, even if I go with thinking of these things as 2 co-primary end points, that's the capitalization on the multiple testing issue that I might have advantaged by knowing about this futility analysis the penalties that I would apply wouldn't account for that sort of a discrepancy.

Marcio, in hindsight, did you -- what were sort of your the futility sort of threshold that you set? And do you think that -- have you in hindsight sort of recognize what perhaps that was flawed about that assumption?

Like we make -- like it's very easy, right? Sometimes we don't like the outcome, then we say the decision was wrong. It's actually decisions are a priority kind of always right and then we judge the outcome here is like -- can you go back and say, if we hadn't changed anything, it would be positive. Therefore, we made the wrong call. Now I think the call we made was scientifically sound just like Chuck just mentioned, asking about what do we know about the drug. And we know it act pretty fast, like we have very high concentrations here as we expected, right? And a minor change, I completely agree with that, would be a time point assessment.

Now when you go back and recalculate knowing the results was the probability of being futile, it's actually not that small. Most people think when you're like, "Oh, that is a futility recommendation, you are on the 0.001% probably not being successful." That's not the case, right? It is actually -- you're making an assumption on that point in time. And it happened. I think it's I'm glad we didn't stop. I'm glad you were like very enrolled on this study, pretty much fully enrolled on the study at that point in time, which allowed us to finish. But I don't think like sitting here and saying what if is actually very helpful. It's like they said it's positive.

And, I think we're out of time. I mean, one final question, Marcio, I had, maybe did you perform sensitivities including things like jump to reference, which is arguably the most conservative for things like the original primary endpoint.

Yes. And you can -- yes, and you can imagine it's sensitive to stress as well, right? And we're looking to other things, I think that Chuck mentioned, like we remove all the covariants and rerun. We added each one of them and rerun like things that you could say, is there anything that could break this, which for us was important, like is there -- are we being misled by the results? And the answer is no. This is just a very strong result. And to be honest, I'll end with this, Chuck, like I know we all care about like the markets, definitely our clients do, and I appreciate all our investors. But there is nothing for these patients out there.

And ultimately, that's why we are developing this. So this is a very strong drug that's going to give a lot of relief to a lot of people, and we're just happy to be in this position to have the discussion with the FDA.

Okay. And so with that, Chuck, if you can give me sort of 1 or 2 minutes, just an overview of everything that you learned today because you sort of gave an assessment you felt the data step was strong. We've learned some more things from Marcio in the course of the call, which I don't think have necessarily been that dramatic, but they sort of add to the body of knowledge that we have. And so when you're leaving this call, how do you come out feeling about the robustness of this data set?

Yes, to both summarize and update slightly, strong analysis strategy. I wouldn't have suggested anything different. So I don't fault them at all on the analysis strategy. There are some technical details we haven't talked about on this call that were chosen that seemed to be pretty conservative and would lead to robust analyses. So I have absolutely no problem with the analysis strategy.

The potential minor red flags, of course, are changed in the outcome. The relatively high rate of missing data, tipping point analysis that wasn't continued all the way to the end and the sort of curiosity about the futility analysis. And I feel pretty reassured about all those. They did a large number of sensitivity analyses, some preplanned and some not preplanned. And I think that's important because, again, you don't want to be depending on one single model for data that's missing not at random, again, as brought up by one of the participants in this call, especially when the rates are high. So it is important to try different mechanisms. And I'm also convinced by the fact that even when you stress test the system, the resulting P-values are relatively small.

Okay. Chuck, that was really helpful. And Marcio, thank you very much for taking the time and accommodating us and being willing to sort of come up with a gun both from myself as well as Chuck. And so with that, we'll let everybody go back to their day.

Sounds good. Thanks. Very nice meeting you, Chuck, and thanks, Doug for everything.

All right. We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. And it's my pleasure to have Marcio Souza, joining me today, CEO of Praxis. Welcome, Marcio.

Thank you. Thanks, Andrew. Appreciate it.

Maybe really briefly because we do want to -- I do want to tackle a lot of things. Maybe walk through the -- what you're working on in the pipeline and milestones we can expect over the next 6 to 12 months, that would be helpful to start.

Absolutely, and it's always a pleasure to be here. Like there is always a lot. I feel every time we talk that there's a lot going on with the company, and we're very pleased and happy with that, but it still remain quite humble on the heels of a very successful essential tremor readout on both studies. So we have that filing coming up, hopefully early in the year, by early in the year. A number of epilepsy assets progressing, including our DEE program with relutrigine. First for a rare indication or 2 rare indications for SCN2A and 8A. Those are coming up. The interim analysis, we're doing that study kind of right now. And by right now, I mean in Q4. We'll continue to recruit quite nicely, may I say, on the larger study, which we call EMERALD, which should read out next year. And in between, assuming that the interim is going to be positive here, of course, would be filing an NDA for that indication. So the next -- if I restrict to the next 6 months, 2 potential NDAs and 2 potential readouts.

And then you also have the focal epilepsy...

Yes, yes. And then another readout for focal epilepsy. Thanks for reminding me of that as you can see, there's a fair bit.

Okay. Very good. So I did want to tackle Essential Tremor to start top of mind of many people so far. I'm sure you get this question a lot. But to begin, you did have this original interim look -- and by the way, congratulations on a successful readout. This interim readout was determined by the DSMB or DMC by futile. How do you reconcile the turn of events between the 2 incidences?

Yes. It's pretty -- and maybe just to recap, right, so early February last -- of this year, there was an analysis done by an independent data monitoring committee assessing what was expected to be 50% of the patients on this study. The idea of conducting that analysis to begin with was there was no successful Phase III study ever in essential tremor for a drug. And faced with a situation like this, we try to learn as much as possible as one goes as we went through. Based on that analysis, the committee came back to us and said it's unlikely to be successful, which we call futile.

I think the first misconception is that when someone says it's unlikely to, they don't mean it's likely will not, right? And it's not a certainty. It's actually expression of a probability on that point in time. We know what happened. It didn't, right? It was very successful at final. So how do you reconcile that, I think, was the -- your question is by going back and actually asked the question, why? And the why here and in most circumstances like this would be pretty simple if people actually continue as we did, it was too early. I think that, that's the simplest and to be honest, the most accurate situation happened was planned at 50%. When you look into the final end, it was actually around 40%, a little bit over 40%. When you consider 40% is pretty early on a study that was fully powered at the end and with the variability at that point in time, with the understanding that they had of the data, they could make no other choice but to recommend us not to.

Why haven't we stopped, right? That's the other question. If I can hijack your question for a second here. Oftentimes, you're asked why haven't we stopped. And that is an even simpler answer. We were basically fully enrolled at that point in time for this study. So it becomes more of an opportunity cost type of situation where the risk of not continuing was pretty easy to determine, right? And the opportunity of continuing was actually pretty easy to determine as well. Considering the investment was so small, but the actual asymmetric upside was so large, we chose to continue.

And then the last thing I would add there, the previous study was at 8 weeks was pretty clear at 8 weeks, and we knew there was some variability in general with these patients. So we wanted to get to that answer like very clearly. And yes, here we are.

Great. Well, you made the right decision. So one more maybe question around that front. If DMC determined as futile, can I infer that the placebo-adjusted change on modified ADL was maybe, let's just say, 0 or worse in the first batch of 40% of patients, meaning that the next 60% or so patients, maybe their placebo-adjusted delta was closer to 5 for you to show around a 2.6. Is that kind of the right concept?

It is not, actually. The placebo-adjusted difference there, well, number one, maybe to clarify that and particularly with this being a webcasted call, there was no point in time that placebo was better than drug on this study at interim or at final at any time point. I think that's super important to understand. There are 2 concepts, right, that determine -- well, there's one concept, but 2 components that determine the actual p-value in this case or the probability there is one is how placebo and drug do, also how the variability does, right, at that point in time. And you can get in a very early look, the standard error can actually play a bigger role or it always plays the same role, but in relative terms, a bigger role for that smaller sample size. That's why we tend to power to a given effect size at a given size of the study. That's why the concept is just was too early.

We see a more stochastic than actually increasing here. It's all to say or to translate that it does vary a little bit every several patients that you add to the study, which is not uncommon. It's actually pretty common in several studies, which the precision of the final gets improved as you go. So it was not negative and then became positive, was positive and became more clearly positive at the end with more power.

Interesting. Okay. And 2 weeks prior to unblinding the data, you did make a couple of tweaks adding 2 hypothesis changes to the SAP plan just slightly. Did you already notify the FDA back then before you top line the data? And did you hear feedback from them that it was okay? Or is that kind of the purpose of this -- one of the purposes of this upcoming meeting that you have in Q4?

Yes. So to -- I think what Andrew is referring to, right, a few weeks before the disclosure, we updated ClinicalTrials.gov with the full hypothesis for these studies. It meant to serve several like reasons or several masters, one could say. One, wanted to make exquisitely clear that all these changes were done like before any knowledge of the data, before database lock, before everything. So that's one of the reasons why. Even the ClinicalTrials.gov in itself posting has a period that we submit and then gets published. So it was not exactly when you're seeing.

What we chose to do as well after we finish all the simulations, after we finish the updates to the statistical analysis plan and the protocol and implement the protocol and get the IRB approvals and got the signatures and so on and so forth was to inform the FDA of all the chains through filings to the IND as is required in the United States, but also for formal communication to the agents about the chains in which we actually notified them on when we're planning to lock the database, which gave, of course, an opportunity for interactions that, that they chose not to exercise, but it was all done several weeks before, as you would imagine, then when the post ClinicalTrials.gov became like up or available. So all of that was done.

Okay. And bottom line, as it stands today, the degree of FDA alignment you have around the regulatory pathway is both studies needing to succeed is how I understand it, using the modified ADL11, FDA is on board with that. Is there anything else you would add that you have alignment as we think about the regulatory review of that?

Yes. So there are a couple more things there or that might be important. So June 2023 was our end of Phase II meeting with the agents based on the Essential1 program that was the prior that served as the hypothesis to be confirmed as it was in the Essential3 program. So during that meeting, we agree on a number of things with the agents was the 2 studies, the design of those studies, the safety database, and that's something we have not mentioned yet and what would be necessary for an NDA filing. And they quite explicitly asked us to very specifically calculate the mADL11, right? So that calculation where you actually use 11 items instead of the 12 and you calculate to 3 was actually a very strong recommendation. One could argue a mandate by the FDA. So that was an alignment very clearly back then and 2 prospective studies versus 1 prospective study, and that's why we've done those 2 different studies. Also agree on the design of those, meaning they were very supportive on one study being a parallel group and the other one being a stable responder randomized withdrawal study. So that's why we ran that way.

Okay. And then one clarifying question then. Do you have buy-in necessarily at this juncture to do a week 8 primary analysis versus week 12, which was the original and then to do the analysis on an mITT basis relative to ITT?

Yes. So separate those 2, right? The mITT basis for here is being on the protocol and the analysis plan and everything from the beginning, it really doesn't matter. And I mean it doesn't matter because the way the model is specified, I'm more than happy to take that offline because it's highly technical. They would result on the exact same like number on this case. But yes, the answer to that question is yes. The choice of the time of the assessment is always the sponsors, right? We know that it's acceptable to do 8 weeks or 12 weeks. We did change, I want to be incredibly clear about that, from 12 weeks as assessed at the average of day 77 and day 84 to day 56. So pretty minor change, but maybe even more important than that, the study was successful at every time point, including the one that was changed from. So maybe...

You didn't need to change it.

We didn't need to change it. Yes, that's another way to think about it.

Okay. And did the study succeed on an ITT basis across every time point as well?

Yes. As I mentioned before, and I know this is not the easiest concept to understand. Mixed model repeated measure requires the term to change in order to use the term, meaning there is no term, there is no data between 0 and 14. And therefore, the estimation for the ITT and the mITT are identical, mathematically. So the numbers are the same.

Okay. So now you have a meeting scheduled in Q4. When do you think you'll come back to the Street with a response? And what exactly are you going to then ask the FDA?

Yes. I think the question, so we have the meeting confirmed as a pre-NDA meeting face-to-face with the agency this quarter. I know the quarter is getting shorter by the minutes. So there's only so many days left.

Is it December or...

I think it's fair to say it's this quarter, which doesn't have a lot more weeks left, right, effectively. And I don't think we're going to have Thanksgiving together at the agents, although I would welcome sharing with them.

The key question is always about the evidence. Like if you go back, and I know you know this, but maybe for the audience, every pre-NDA meeting on an approved drug is available publicly. Just go back and check which questions are asked. So of course, we're asking about the package itself. And there's normally a bunch of, I'm going to call administrative questions about the structure of the filing and so on. So we're asking some of those as well. I think it's proper at this day and age that we just wait for the minutes. Obviously, 1,000 different scenarios here that can play out, but you should assume that the base case is that we wait for the minutes, 30 days later, we make a communication. We expect that communication to be when we're filing the NDA based on the discussion with the agency.

Great. And do you envision the FDA -- investors like to ask me what kind of degree of analysis will the FDA do in this pre-NDA meeting? Is it pretty deep? Or is that something -- is it more of a review issue once this is accepted -- in your view.

I personally never seen the FDA run an analysis on a pre-NDA meeting, right? But I'm not saying it's not possible. Normally, what happens is the sponsors, our case submit the briefing package. In case of a pre-NDA is 30 days before the meeting happen, it's a very comprehensive package. I think we call meeting materials, nobody used to call briefing book. Very, very comprehensive. It allows the agents to really explore the question, right? It's our position on the question that we are asking, we think, again, it's pretty straightforward. Could they and would they ask questions for us to better inform their review of the NDA. Possibly, I think that is quite reasonable. We try to ask ourselves which questions could they ask with sensitivities could they be interested on understanding and we included those already on the briefing package so to make the discussion more effective.

And so we'll be patient about that. You'll submit it in early 2026. Let's just say it did get approved. I'm hopeful it gets approved. How many sales reps do you think you'll need to launch this drug ultimately?

The Essential Tremor, there's one drug approved, right, propranolol, as we know, it's a beta-blocker, being approved many, many years ago on a number of cases that were submitted to the agency. If you go and look into the file, you're going to find that it reflects what happens when you take propranolol for this disease. It's very ineffective. Tolerability is a major issue, and it's really used, unfortunately, by a very small number of patients.

There are 7 million Americans living with Essential Tremor. About 2 million to 3 million of them are actively seeking treatment because it is to a degree that impacts significantly their activities of daily living, which is why the agents asked us to measure that as previous. So when you look back to those numbers, it's obviously incredibly large market. The beauty of this market, one is that we understand this incredibly well. During our recruitment campaign for Essential3 program, we built a database with over 200,000 patients. And it's not wrong, it's 200,000, and that was a relatively small company that we are and we were back then, which gave us great insight on how to reach these patients, how to understand, how to get them in.

When you project to what can be done between now and the launch, and let's argue in about 12 months or so, we believe we can get to a much, much larger number there. And what allowed us to do as well is to understand where those patients are being seen, how are they being treated? And the vast majority of them are neurologists, non-movement disorder physicians. Actually, one could argue fortunately, another one could argue unfortunately, I'm going to pick the fortunately because there's not enough movement disorder physicians to see patients even if they want it, and the neurologists are more than capable of caring for those. To cover the 13,000 to 14,000 neurologists in the United States with the ramp-up, we expect to be with a very robust DTC campaign, we need about 300 or so people on the ground to reach our midpoint of the estimate for the launch is around $8 billion to $10 billion in peak sales. So to get to that point with this drug, that's why we believe we have to start. Obviously, that's not where it end, but it's where it starts.

And maybe one more question. We have 5 minutes left. But I've spoken to doctors and neurologists and the feedback for some of them have been the week 8 efficacy looks stronger than week 12. There's a slight waning of effect. That leads me to think this open-label data set or study that you're enrolling could be meaningful. Do you plan to share data cuts in 2026 to show us the durability of that?

Yes. So the first thing I can say it's not a durability of effect at all, like if that's the concern here at Summit, it is a variable condition. When you have the most effective, it's not even close to be the most effective treatment for Essential Tremor. This that folds better than anything that even being attempted here. I think it's the champagne problem to talk about a point estimates that vary by 0.5 points between one and the other and humans love picking on the little variability versus looking to the possibility here, was not only that they were better on the 11 items, actually 12 because the ADL was positive as well, but they were better on the PGI, on the CGI, on the severity and on the improvements on those. I challenge anyone to actually show any other drug recent history in neurology with even a close effect. When you ask patients, they are quite desperate actually to be on the drug. And when you ask the majority of the physicians, they're quite desperate to start prescribing this drug as well. But to answer your question more directly, yes, we're going to continue to show data, and I think people are going to continue to be quite convinced on how effective this drug is.

I would love to talk about relutrigine because recently you announced you all plan to do an interim analysis. So can you walk us through -- this is for SCN2A and 8A, your 2 rare DEEs to start. Can you walk us through the scenarios of the interim? Is there a futility analysis or something like that? Is there upsize the study continue as planned? Walk us through the various outcomes.

Yes. So the relutrigine program that we are developing as a precision medicine for DEEs in general, like, I think it's important to conserve the entire program here, right? So we had phenomenal preclinical work, which led us to test first on SCN2A and 8A, about 5,000 patients in the U.S. and I think 15,000 or so addressable in markets that have robust market access mechanisms around the world.

We were granted breakthrough designation after a very successful Phase II. We also had a conversation with the agents about what's next for this program, and that is why we are running the EMERALD study to serve as the second for another indication. It's going to become important in a second why I'm saying that. In the breakthrough discussions, we were asked how to accelerate this program. And we chose to do that by looking into about 70% of the patients on this study only, so there is no future assessment, there is no resizing or sample size reestimation assessment here. The only choice is to progress to final or to declare successful. That would serve if successful, either at final or at interim as the base of the NDA for SCN2A and 8A.

Once that NDA is approved, hopefully next year, we would have a second study with EMERALD that would serve as the base for an sNDA for the larger indication on DEE. A big part of our work has been understanding the patients, the patient needs, developing drugs that are not only highly effective, but quite convenient for those patients to take and instead of relying on the same old industry standard, do things as slow, burn as much capital as you can actually accelerate development. And EMERALD is enrolled really, really well. I can tell you with high certainty that's going to actually read out next year, which means we're going to be in a position to file that sNDA very quickly and very, very likely be the first approved drug for DEEs in the U.S., which is a $3 billion to $4 billion opportunity. So just put the [ 2 and 2 ] together, and I think we're all going to realize how big of an opportunity for patients to get better, but also for shareholders to do well and for all of us.

I see. As you're talking, I just realize there is another competitor evaluating broad DEEs, but you're ahead of them or you should be ahead of them with the EMERALD reading out kind of...

Arguably.

Okay. And so back to the interim, maybe one last question. I think you're going to do this unique analysis with the log transformation. I don't know if investors are -- I don't know what that -- Julian tells I've only seen that in one epilepsy readout, but will you plan to share the traditional seizure reduction percentage drug versus placebo? And if so, what is a positive strong result to you?

Yes. It's about half of the drugs that actually have being analyzed that way for epilepsy. It's a property of highly skewed distributions, very common, 0 controversial analysis on that regard. You can back transform to the percent. I think purists, mathematicians would say it is an approximation when you back transform, but we will show that. And most people just believe that is exactly the same numbers because zeros cannot logs, as you know. So you have to add a factor. So there's always an underestimation versus an overestimation of the effect. I want to know exactly why you can do it. But yes, it's being done one of the most successful, if not most successful drug in DEEs, actually did exactly the same analysis got approved. And I don't think they ever got that question because there was no one with [indiscernible] lite trying to feed an incomplete narrative. So that's a little bit of [ bias ]. And I think it's important that we just say when it is.

Okay. If it's fast, that's great.

Exactly.

All right. Thank you very much for clearing up a lot of questions for me. Thanks, everyone, for listening.

Any day. Thanks.

Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Essential3 Topline Results Conference Call. [Operator Instructions] Please note that today's conference may be recorded.

I will now hand the conference over to your speaker host, Dan Ferry. Please go ahead.

Good morning, and welcome to the Praxis Precision Medicines Essential3 Topline Results Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com.

Please note 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 time lines and financial projections. While these forward-looking statements represent Praxis' views as of today, they 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 on 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.

Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis; Tim Kelly, Chief Financial Officer; and Steve Petrou, Chief Scientific Officer. After our prepared remarks, there will be a brief question-and-answer session.

With that, it's my pleasure to turn the call over to Marcio. Marcio?

Good morning, and thank you for joining us today to discuss the exciting results from the studies under the Essential3 program and our path forward. I'm going to be making forward-looking statements on today's call, so please refer to our updated disclosures on the SEC website.

The Essential3 program for ulixacaltamide hydrochloride, as you all now know, was the first Phase III program ever to be positive in essential tremor for a drug. Both studies under the Essential3 program met their respective primary endpoints. Ulixacaltamide was generally safe and well tolerated with no drug-related severe adverse events. The result of all of that is that Praxis has submitted a pre-NDA meeting request to the FDA, and we look forward to hearing back from the agents to move this program forward.

Essential tremor affects an estimated seven million people in the United States alone. It's puzzling that there is no specific drug approved for essential tremor that was developed for the condition, and we're here to change that.

But before I dive deeper into the trial and its results, I need to express my gratitude to all the people living with essential tremor who participated in our clinical studies, to their families who supported them, to the advocates who guided our work throughout, and to everyone at Praxis, at the central site, the PIs and sub-Is that carry through such an ambition program to fruition.

The scientific hypothesis underpinning ulixacaltamide is very clear in relation to essential tremor. Modulation of this important network in the brain by inhibiting T-type calcium channel block is fundamental.

Now before we move forward and talk about the results, I believe it's worth taking a moment to walk through the developments of the last few years. Just a little bit two years ago, we read out our Phase IIb Essential1, which helped us establish the endpoints that should be used in a late-stage program, aka Phase III, the dose that should be used and many other aspects of the operation of such studies.

We moved from there to have several discussions with the FDA, particularly centered around an end of Phase II meeting and subsequent communications where we're seeking and gained alignment on the Phase III program as it relates to the endpoints, to dose and the overall design.

We started the Essential3 program shortly thereafter. And from the get-go, we've seen very sustained and robust interest by patients and enthusiasm by physicians. It was incredibly ambitious to recruit two simultaneous studies at the same time.

As we fast forward to earlier this year, Study 1 was subject to an interim analysis. And when examining the study at that point in time with that sample size, the independent data monitoring committee, which was bound by very strict rules, recommended that the study was unlikely to meet its primary endpoints based on the assumptions at the time. In other words, a futility recommendation.

Due to the late stage of recruitment for this study, the fact that they were intrinsically linked to Study 1 and Study 2, and our general belief that faced with uncertainty being the first on a position to finish a Phase III program, we decided to continue these studies. Praxis was not unblinded to any of the analysis or any of the deliberations that the IDMC had leading to their recommendation.

Between that point and last month, we conducted extensive simulations and analysis on the blinded data. We consulted with a number of statistical, clinical and regulatory advisers, and we decided that the most prudent thing to do was to refer back to what we knew from the Essential1 program that was the ability for ulixacaltamide to positively modify the disease when patients are exposed between baseline and day 56. So we made the decision to change the primary endpoint to day 56 from day 84.

We also simplified the key secondary endpoints based on prior feedback from the FDA. All those decisions and the change that they generated on the protocol, on the statistical analysis plans and on the postings at clinicaltrials.gov, as you might have seen, were done without any knowledge of either the interim analysis specific results or any unblinding of the data.

From that point on, we are here today. In the last few days, we unblinded the study and we examined the data, and we're very happy to say that all prespecified analysis for the primary on all four hypothesis that were generated in this program were met.

What are those hypothesis? So the first one was the superiority of ulixacaltamide versus placebo on the parallel group study at day 56. The second one was whether or not ulixacaltamide exposed patients for eight weeks in a blinded lead-in were able to keep the response in a superior manner than patients who are switched to placebo. That was also positive. Because of the unique nature of the Essential3 program and the fact that not only blinding was happening within the trial, but also within the trials, Study 1 and Study 2, we're able to combine the arms of those studies. And that's where hypothesis 3 with an overall combination, and hypothesis 4, which is contemporaneously using the arm on placebo from Study 1 with drug from Study 2 were done. All hypothesis resulted in positive statistically significant results.

So, now let me walk you through some specifics from each one of these studies and from the next steps. So Study 1 was 12 weeks in duration. and patients were exposed for ulixacaltamide for all 12 weeks or placebo for all 12 weeks. They were randomized simultaneously between Study 1 and Study 2 from the same pool of patients. We made Study 2 blinded for patients, personnel in the study or investigators in a very unique way during the totality of the study. Patients at the end of week eight that met the criteria for response of 3 points on the average of day 49 and day 56 were then randomized to stay on ulixacaltamide or to switch to placebo.

So, let's talk about Study 1 results. The primary prespecified endpoint was the change from baseline to day 56 on the mADL11, analyzed using an MMRM model. Afterwards, if that was positive, the prespecified sequential key secondary endpoints was the rate of disease improvement throughout the study, the PGI-C and the CGI-S at day 56. The baseline characteristics and demographics for those patients were well balanced between ulixacaltamide and placebo and represents a very severe affected and representative of the United States population with essential tremor.

Patients randomized to the ulixacaltamide arm on Study 1 observed an average of 4-point gain after 12 weeks. This is a very large and very robust change. When compared to placebo, as you can see on this slide, those results were highly significant. All key secondary endpoints were also significant, both clinically and statistically. The rate of improvement throughout all 12 weeks the patient global impression of change and the clinician global impression of severity.

Importantly, we have conducted a prespecified tipping-point analysis to test the robustness of the primary endpoints achieving such remarkable statistical significance. That sensitivity was also positive, resulting into a very small p-value, which confirms the robustness and statistical stability of the results we are seeing here. It was also impressive to see that not only ulixacaltamide acts very fast, as we can see here in the chart, as early as two weeks when the first assessment was done, but throughout the study. That includes day 77 and 84, as we discussed, being the time point by which the prior primary endpoint was assessed. If no change have been made to the time point of assessment, the study would still be highly positive.

Study 1 was also robust in terms of all the other subgroups. When you look into age, sex, concomitant use of ET meds or the three stratification factors being propranolol at baseline, presence of intention tremor or family history of essential tremor, all of them did not influence statistically the robustness of the results being all very clearly in favor of ulixacaltamide.

With those good news, let me move to Study 2. As we mentioned, Study 2 was measuring the ability of patients who responded to ulixacaltamide to stay responding. So the rate and the proportion of patients who maintain the response as compared to placebo was the primary endpoint. Those were supported by some key sequential secondary endpoints as the rate of disease improvement as in Study 1, the PGI-C and the CGI-S on the same period. In terms of baseline demographics, the randomization worked really well between not only the arms on Study 1, Study 2 and continue to represent the population.

So how did the results come out? Study 2 was positive in the primary endpoints and on the first key secondary showing a very robust maintenance of response on patients with stays on ulixacaltamide compared to placebo. That's incredible and makes us incredibly happy to have now two studies that are likely to constitute substantial evidence of effectiveness to submit an NDA.

It's also exciting that hypothesis 3 and 4 resulted into positive results. Those hypothesis supports and strength the data we've seen already. When we look into hypothesis 3, which compare the sum of the arms on drug between Study 1 and Study 2 versus placebo, the results were highly significant and highly meaningful. When we look into hypothesis 3, could only be possible in a study that is done like the one we did here under the Essential3 program, which kept all the arms and a finance 2 study blinded. We could test whether or not patients on Study 2 on the first eight weeks receiving ulixacaltamide when compared to the placebo on Study 1 had a significant difference. That is de facto a replication of Study 1 on the same time. And what we see once again is a very robust replication of what we've seen on Study 1.

So let's talk about safety in this patient population. No change in the overall safety profile and no new signals were identified. The most common treatment-emerging AEs, patients in ulixacaltamide were constipation, dizziness, euphoric moods, brain fog, headache, paraesthesia, insomnia and fatigue. And we're going to talk about the discontinuations and the specifics on these rates in a minute. The majority of the treatment-emerging AEs were mild to moderate in severe. No severe adverse event was related to ulixacaltamide, and no patients die during the study. When you look into the disposition of this study, which is.

Relevant for the safety analysis, patients who received at least one dose of the drug or placebo are considered in the safety analysis. For all the other analysis we discussed today, patients had not only to receive one dose, but to have a post-baseline assessment, which is very common practice and has been prespecified and reviewed in all the documents that we had and formalized with the FDA.

Now speaking about safety. The vast majority of the patients had a treatment-emerging AEs. Majority of them were mild or moderate in nature across the board in the different arms or studies. A small proportion of patients had severe adverse events on either ulixacaltamide or placebo. No serious AEs were related to drug in any patient in this study. Approximately 30% of patients receiving ulixacaltamide and approximately 2% on placebo discontinued due to treatment-emerging AEs. And the overall discontinuation in the study due to different cause were around 35% for ulixacaltamide treated patients.

In terms of the adverse events themselves, as you can see here in the table, the top four were constipation, dizziness, euphoric mood and brain fog. Those were all expected for such an active and potent drug as ulixa is. Those are very common across CNS active drugs, and we believe that physicians are going to be able to manage in the real world for this population.

With that in mind, I want to conclude those remarks by thanking everyone involved on this study. It's not many moments in life that we are the first to develop a drug specifically for a condition with such a high unmet need affecting millions of Americans and to have a package that we believe could lead to an NDA approval in the near future.

Now I'm going to open the call for Q&A. Operator?

[Operator Instructions] We have a question coming from the line of Athena Chin with TD Cowen.

Sorry, this is Ritu.

Hey, Ritu. Sorry.

Okay. It's my fault and our registration fault. Congratulations on the data this morning. Guys, it sounds like the variability and the low end from the dropouts contributed to the -- for lack of a better word, bad luck on the interim. Can you talk a little bit -- first of all, correct me if I'm wrong and if it wasn't variability and low end on that interim. But given the dropout profile that we've seen, can you speak to anything that was done or could be done in the real world to manage some of these brain fog and these dizziness symptoms and the transients and sort of other clinically relevant aspects of these side effect profiles in the real world that could be improved?

Yes, absolutely. And thank you so much, Ritu. Like we're ecstatic and excited about being able to help these patients with quite definitive results here. I think we're there in terms of like bad luck, I would say, it does strike from time to time. But today, I think what we talk about is not luck, it's certainty and the certainty is with the final results that we have for both studies showing very clearly what we're doing with for these patients.

When you look into such an active drug, right, like incredible, arguably larger-than-expected effect, that is an expectation that some patients might be overshot in terms of the group exposure dose, whatever it is here. Not uncommon to think and we talk to hundreds of neurologists and very, very, very common in neurology for them to, after a drug is approved, take matters on their own hands as they should as treating physicians and look into the patient versus the cohorts.

As we look into a trial, we're looking into the cohorts, what is the best thing for the cohorts. And that's what we've done here. And I think it's undisputable that, that call was correct. When you move to the real world, there's better counseling can be done because now we know the drug is effective. So, counseling a patient on an effective drug is very different than on a likelihood of being on a drug that might or might not work or placebo and multiple things that can be done to minimize or even eliminate that. One of them is time. And we know that the more time you spend on the drug, the more accustomed, I would say, to some of the side effects, but there's other ways to manage as well, definitely better hydration on this older population.

If we take the very worst-case scenario here would be helping five million patients in the U.S. I'll take helping one person every day of my life. I certainly would take five million. But we do want to help as many as possible with this drug being the only game in town. So we're going to work very diligently with physicians to help them guide the way if you are so lucky on getting the NDA approved upon submission to the FDA.

And our next question coming from the line of Yasmeen Rahimi with Piper Sandler.

Congrats to the outstanding data and honestly, for not giving up on the program and really plowing through really remarkable and a great decision made for patients and for the company.

My question is, team, given that you have requested your pre-NDA meeting with the agency with a very data-rich package, what additional analyses are you planning to complete as you head into the meeting? And then how do you plan on sort of communicating sort of the next steps with the Street?

And maybe one other. If you file your NDA in early 2026, how do you envision sort of getting commercially ready? So I would love to learn sort of what's on the to-do list between now and the next few months?

Thanks, Yas, and thanks for all the ongoing discussions throughout the years about this program. I sincerely appreciate that.

Very happy to now talk about what is next, how do we get this drug to the market, right? I think the first important step here is that there is a lot of change happening in the United States, and we're very happy to know because these statements of facts of opinion that the staff of the FDA have been working with us from the end of Phase II is there from like pretty much all levels. Like they understand the conversations we had. They've been guiding us along the way and to be very responsive about our interactions.

So we do expect to get the meeting pretty soon. We -- there's always a number of other like sensitivities and things like that, that can and should be done throughout. But the bulk of that, I think we were 15 out of 10 on our slide deck this morning. I hope you all agree. We put a lot of that out already, right? Like the classical like is there a subgroup here that is Q and the answer is no. I think that's a very classic like this works across the board for all those patients. Is there anything that will change the original guidance for safety? And the answer is no.

Then the things you don't know because we haven't communicated, we have concluded all special population studies, renal and hepatic. We have completed all the preclinical package. As a matter of fact, we have already finished 80% of all the documents. that are related to the NDA. We never stopped because we always understood very clearly the need. So in very advanced stage of preparation for the NDA. We have a specific CMC meeting with the FDA, which is always very important, particularly at this day and age, to understand what else we could do.

So, I can give you the assurance that, number one, I may actually have to say that it's an outstanding team, right, that we have here because we hear companies that are not even close to where we are in terms of submission of an NDA, and they already like way beyond the point. So the team was very diligent with very little resource since we are, until this point, a limited company, completing 80% or so of the documents for an NDA is no small feat.

So, we're very confident that everything the agents guided us so far, we have done. We are in a very good, I'm going to say, relationship with the agents in terms of like being very transparent with them, being a very direct dialogue. It's good. The neurology is kind of our house in a sense there. We have several programs. They know how serious we are scientifically. So we can't state for the agents, but I'm grateful on how much guidance they gave us. I'm grateful on how much time they gave us throughout the years, and we're going to tell you all soon. Once we get there, then we're going to talk about how to maximize the value.

I think there is -- no one would doubt and certainly, I believe your model would support us the lowest end of the expected sales here is at least on the mid- to high single-digit billion. And the very reasonable estimate is on the mid-teens for billions for -- if you use just regular like pricing and penetration assumptions. So we always took that in mind when you are planning manufacturing, when we are planning other things, and I look forward to discuss all of that with you and everyone else very soon.

And our next question coming from the line of Joon Lee with Truist Securities.

Congrats on the really impressive results. You have indeed put out a lot of details even for this top line data disclosure. On Slide 14, specifically, the efficacy peaks at around day 49, 56 and starts to decline a bit thereafter. Any reasons for that? And would the study have hit stats at day 84 without any changes?

And then are there any flexibility in the dose titration to help mitigate some of the AEs that led to the discontinuations?

Yes, absolutely. I likely would disagree with your statement that like if you look into the confidence intervals within each one of the points, right? And I know you are good students of science and statistics that is the precision is just within for all those time points. So the effect is actually largely and very large maintained throughout. Very important to notice that the every time point is statistically significant, right, that they all favor drug. They all to the right of zero here on Slide 14, as you mentioned. So no doubt whatsoever there.

On the other side of the question, as you know, we hit it out of the park in terms of how fast it starts, right? By day 14, by two weeks of treatment, this effect was established. So it's not unreasonable, and we did talk to a number of neurologists to think that for some patients, they might just slow down a little bit. It's a lifelong condition. Patients were living with essential tremor in this study for 30 years, right, for about a little bit less than half of the median life expectancy in the United States, they've been living with essential tremor. So maybe another month that's going to be up to them, and I'm sure they're going to do it. You know they're going to do it because we're practicing before, and that is likely going to help for some patients. But for the cohort, for the 70% or so that get to incredible benefits without any detriment that I'm sure they're going to go full-blown as well because what we hear from patients is that they want the effect. They'll be waiting for it.

The most emotional part of this process was receiving Patrick's quotes that is in our press release. When into interacting with each one of those patients through the study to getting letters from them to the central sites to the PIs and telling us, you change my life. I can go and go back to something else and holding that excitement. I share this excitement now is going to be throughout the United States where we have plans for this drug. But not going to keep going there because I think you've got the gist and I appreciate the question and so on.

Our next question coming from the line of Yatin Suneja with Guggenheim.

Guys, let me add my congratulations as well. Truly a positive surprise, I think, for us and for many of our investors and stakeholders. So congratulations on the team.

I have two questions. I think those will help some of our investors because we're definitely getting a lot of things on that. So the first question is on the NDA requirement. I know, Marcio, you touched on it, but could you maybe talk about what is the ICH guidelines for something like this? Is there a particular long-term safety requirement for a disease like essential tremor that affects many people, if you can comment there.

And then one more question, if I may. And again, this is an investor-related question or driven question. What alignment was reached with the FDA when you made the protocol changes on either the stat plan, whether you can evaluate on an mITT basis, ITT basis? Anything you can provide, that would be really helpful. Again, thanks very much.

Yes. No, absolutely. And thank you. The ICH guideline for safety itself gives a range, right? So what we've done instead of taking the liberty there is actually we had a discussion with the agency and like knowing the safety profile of the drug, which is the same between the multiple Phase -- is we conducted the Phase II, what was the requirements. And what they very clearly stated to us is 100 patients for one year and for 300 patients for six months and then 1,000 total exposures. So we have zero concerns about getting that package available for the agency. That is also considered what the minimum ICH guideline, which should tell you their impression about the safety of the drug in general. So no concern there for the submission itself.

There were a lot of conversations that we have both formally and informally with the agents throughout the years on this. We have a very good understanding on how they see this analysis. We have submitted and clarified the analysis plan with them. And that's obviously great from your perspective and investors.

But maybe even more important here is that it is largely irrelevant because the trial would have been successful without any change. And we put that specifically on the press release that analysis, just to remind everyone that it really doesn't matter in a sense, right? The trial is positive independently of how it's analyzed on the time point of 56 or 84.

And our next question coming from the line of Jay Olson with Oppenheimer.

Congratulations on these landmark results, and thank you for your persistence in successfully completing this development plan on behalf of patients in need.

Can you talk about your medical education strategy for ulixacaltamide in essential tremor, especially since you're going to be pioneers? And also, how are you thinking about the duration of therapy with ulixa? Or would it be dosed chronically?

No, I appreciate it, Jay. And I guess I'm going to give you a call for headlines next time because I missed the landmark on ours here.

So we've been super fortunate to be guided by a number of experts, number one, and you saw three of them, our three co-leads principal investigators quoted in our press release, and I think you can feel their enthusiasm there. All the members of the eligibility review committee, the help of the study and many others, right?

And last AM, and I'm sure a big expansion of the following one, we had the opportunity to talk to a lot of people about this and how it's going to be used. And I think the answer we get, and I'm sure the answer is going to get when you go out there and ask those physicians as well is right now, it's incredibly frustrating because there's nothing they can do. They know it's getting worse. You might have seen that on our slides on the demographics. Over 90%, about 95% of the patients got worse in the last three years. We've been out there. We've been limited in terms of how much effort we put on this, just as our previous disclosures in terms of limiting the investment. We're going to increase that moving forward. But we are seeing a very responsive, positively responsive like community already expecting.

I'm going to switch to a slightly different topic here. 200,000, over 200,000 patients currently in our database. People who raised their hands and said, I want to be part of any effort to advance treatments for essential tremor. That was with the limited resource a company like Praxis had to this point and with the discipline to really just put so much resource to this one program, right? You can imagine what can happen here with the expansion that we should have with this positive. So we're very, very happy.

And lastly, on the durability of effect, we do have several patients, many, many patients way beyond one year and so on. So I think the chronicity of the treatment here is pretty clear, right? This is a drug that very strongly inhibits a quite important oscillatory like modulator of the brain that leads to tremor and other tremors as well. And it has to be present, right? That inhibition needs to be present for. So it is a chronic treatment, the daily treatment right now. It's likely to continue as a daily treatment for the time being. And I think patients like the idea that it is like once a day, it's not like multiple times and things like that.

A pro anecdote before moving to the next question. We asked patients at the beginning of this study like what is one of the issues that we deal with. And what they said is the fields are too small for these other drugs. So we made all the -- our fantastic CMC team made all the field is larger for this study, like already thinking on compliance, already thinking on making their life easier in the future for commercialization. So super happy with everything, but really been thinking about commercializing this drug all along.

Our next question coming from the line of Brian Skorney with Baird.

Congrats on the great data. Just a couple for me. Maybe I missed this, but can you walk through how discontinuations were accounted for in the mITT analysis? And have you run a tipping point analysis on the results yet?

And then my second question is, I know there are nonscheduled drugs that can show euphoria and there's precedent with type calcium channels for not being scheduled. But given the delta that you see on euphoria, can you discuss any regulatory discussion around evaluation of abuse potential?

Absolutely, Brian. So the -- as you know, right, by the very follow-up of your question, the [ MMRM in MDD ] assumes as a condition of the model that the data is missing at random or a MAR assumption. We prespecified and agreed with the agents that we would conduct a tipping point analysis. And I know the press release is very large, but if you look into the bottom of the table on the Study 1, we're already showing you the results of that tipping point analysis, right?

Tipping points are, as you know, gradual because you keep like going up around to what has been defined as the maximum you should do, that is about half a standard deviation or so in our case, it was around 2.5 points. you normally break or you tip. In our case, when you get there, the p-value was 0.0026. So we did not tip. In other words, as you know, but for the others, not so worse in the call, means it doesn't matter, right? You can really attempt to break by reproducing MAR data pattern here and the data is still incredibly strong. So very, very happy with that.

I think you had a second part of the question that I might have forgotten. Oh, human abuse potential. So the -- we did have that. As you mentioned, we've been discussing all along with the agency. We have conducted a human abuse potential. We are in active discussions about that. At this point in time, knowing what we know about the results of such study, we do not believe that there is here a scheduling requirements. That is not up to us to decide. The agency is going to make that determination at the end. But we believe that have completed all the requirements under the "ICH guideline", we shouldn't be or should be a minimal scheduling there. So everything has been completed in regard to human abuse potential and habitual users study.

We have a question coming from the line of Doug from H.C. Wainwright.

Congrats on the data. I guess maybe, Marcio, as a starting point, I know when you conducted the interim analysis, the Data Monitoring Board had said that there was sort of the potential or sort of ask you to look at the sort of statistical model that was done. Can you sort of talk a little bit against what changes might have been made?

And then just as a follow-up question, I'm curious in terms of the MDD, ADL, the mADL improvements that you saw. Were there any particular domains or sort of areas of the ADL that we saw patients see most improvement on?

No, absolutely, Doug, and thanks for the support as well. So we looked through as I mentioned in my prepared remarks, and we decided not really to move the model, not really to change the model after very extensive simulations. They were based on a number of things, but one premise, right, that the minimum amount of change probably would be the best thing to do here under the conditions we're seeing and ended up being the best here. So there was no change on the structure on the covariates or anything there for the model. Really, the MMRM was there before, the MMRM is now, and you see the terms on the MMRM in our slides as well that did not change.

So now speaking about other things, we have a lot of stuff to continue looking. What made us very clear that it was across the board is when you have four functions regained in average after 30 years of disease. Imagine something and we're no spring chicken, definitely not me or you, Doug, with all respects. And we lost certain functions throughout life, right? They are not coming back. We're not as athletic as we used to be, for example, well, maybe I should speak for myself. I am not as athletic as I used to be on my volleyball times, and regaining those functions are very difficult for neurotypical, normal-typical person for patients with essential tremor to regain function, you must have an impact across the board for those patients.

So while we're going to be showing things and you can imagine that our PIs were like how many papers are out of this, and we estimated about 30 to 50 papers out of everything that was done in this study. So it's going to continue to come and it's going to continue to surprise positively you and everyone else. But as I said before, we are 15 out of 10 on the disclosure. So wait for the next several things to come that are going to support even more.

Our next question coming from the line of Francois Brisebois with LifeSci Capital.

Well, congrats on my side, too. This is quite the story here and the comeback here. So I just wanted to -- a couple of questions on the commercial potential. You've thrown out some sales numbers that are definitely impressive. I'm just wondering what -- you talked about the seven million patients, you've thrown out the five million patients. Can you help us understand a little bit what patients are currently doing, if there's anything out there that's approved and maybe what percentage of patients seek treatment? And then is there a breakdown when you speak to neurologists or to physicians about whether a patient is mild, moderate or severe? And to close it out, obviously, this is kind of a first, but any analogs on the pricing side that we can think about?

Yes. No, no, absolutely. A very, very relevant question for where we are right now, right? Well, the way we've been looking into this in our, I would say, lower case scenario is about two million patients at the TAM at launch, at the point that we are starting to gain some traction there. And that is very conservative, I can tell you. We look to historically, all the work we've done, we conducted about one million patients worth of reviews of records, use of medications, patterns of use discontinuation and so on.

And unfortunately, may I say it doesn't really work like what is available right now, right? They don't stay on Etsy, it doesn't work, doesn't reduce sometimes, they try to stay on propranolol, for example, you saw that about 30% of the patients in the study were on propranolol, not doing much for them, driving a lot of side effects. And you might have seen in our Slide 15 that on top of propranolol, the effect was massive for the drug. So there is no reason to hesitate even on those, right? And the majority of them actually discontinue something else before.

So we look to the TAM here, looking into the fact that this is a family disease. I think what's been happening throughout the years is that people have been hiding from essential tremor because they've seen their parents, they've seen their uncles, they're seeing like their kids sometimes, and they knew what was coming, right? And they're holding back on really jumping to do something because their neurologists, rightfully so, by the way, we're telling them there's not much I can do for you.

Now we're moving to this new era where patients can have hope and should have hope, may I say, and it's going to be like a commercial success, I have no doubt. Now the numbers we threw out there, I threw out there, right, obviously, are statements of our belief in what this can happen, quite informed by all the analysis we've done. When you go for the lowest possible price, this drug should be priced at. And you can pick that number. I don't need to pick the number. It's hard to keep that in single-digit billions. I'm sure when you revise your model later today, if it's not revised yet, you're going to concur going to agree with me. I don't think there's any disagreement. There was ever any disagreement on how large this is.

Take a moment to imagine another disease that affects several million Americans that don't have a single specific treatment approved. I cannot come up with one. So maybe you guys can help me out there. Now imagine what can be out of that in terms of commercial success. I don't think it's very hard to imagine the numbers we're talking about here.

Our next question coming from the line of Justin Walsh with JonesTrading.

Looking at the mean PGI-C results for ulixacaltamide, which were near 3, which I think is minimally improved on the scale versus 4 for placebo, which is no change. I mean obviously, we can see the drug is working. But I was just wondering if you could comment on how meaningful this improvement is to patients, particularly in the context of some of the dizziness and brain fog that some of these patients experienced.

Yes. Very good contextualizing question as well, Justin. The -- like we put a lot of data out there today, right? So we decided at one point that there was like a diminishing return on adding more, but I can contextualize to you something that you should expect in the near future is talking about the improvement proportions. And you're going to be really impressed about that.

Like there are two ways to look into the data from the global impression scales. One is using the continuous variable, as you've just seen here. But the other one and arguably quite meaningful is the way we look into this before by looking to proportions of patients with very significant improvement with much improved with reduced severity in general, and that is quite impressive as well.

What we've seen in the study, what we hear from patients, what we've heard from the experts we discussed with is there was not even an expectation this would improve, right? Like think about, again, the patient population, the age, the overall demographics and so on. It's very hard to increase -- to decrease severity, very, very hard in a global scale, right? Not in an essential term scale. They are healthier. That's the conclusion at the end of the study, and that's quite remarkable. But more to come, good contextualization question for sure.

Our next question coming from the line of Ami Fadia with Needham & Company.

This data is truly groundbreaking and couldn't have been done without the strong execution and persistence. So I congratulate the team for that.

Maybe a lot of my questions have been answered, but I was wondering if you could give some color on when the discontinuations typically occur for patients as in after how many weeks of treatment? And as you sort of look back at the data, how much of that or the timing of the discontinuations around the interim analysis may have contributed to sort of a negative result on interim analysis, but of course, positive data as we look at the full study?

Yes. I mean it does influence, right? So when you have relatively early like a median day 21 for those discontinuations at a smaller sample size with potentially higher variability, like that is just very easy to conclude that it reduce the likelihood, and we're always talking about likelihood here, right, not certainties in terms of the entrant. So, I think, yes, you are right there in terms of what could have happened.

And the other part of the question, sorry for missing that.

Well, I guess maybe just what can be done maybe in the real-world setting to manage the discontinuations and anything you learned from the trial around where most of them sort of accumulate, which might tell us something about the adverse event profile.

No, no, absolutely. I think what is being done, right, throughout the study as we kept things really constant to make sure we had the best estimate for the study. But we know, for example, in the long-term safety study, what can be done is -- and thankfully, they are very simple, right? They're like hydration helps a lot for these patients. I certainly learned more about hydration in terms of like the elderly population than I would have thought in my life and how important that is.

In general, I think the PIs, they were really willing and they really wanted to play with the dog a little bit. Of course, they could not. There was a very clear directive not to do. But we know that, that's going to be happening in the real world for these patients. But it's an expression of how strong the drug is as well. So we knew you might recall in other conversations, we talked about all the expectations here in terms of how potent this drug is. It just came to fruition today.

We will do our best and to help to understand and to guide health care professionals, manage their patients, but it was very thrilling for all of them. I think the first calls we did with PIs, they -- I dare to say they were more excited than we were at one point, which was kind of weird and then we got as excited as they were because they are this suffering and they are touching these patients every single day, and we think about them every single day, but we are not on their shoes. So this is going to be a great partnership to help as many patients as possible.

And that's all the time we have for our Q&A session. I will now turn the call back over to Marcio De'Souza for any closing remarks.

Well, I would like to thank everyone. This is quite incredible moment in science. when we can help patients really by doing the most rigorous hard-working execution, disciplined way to look into outside that one could have. So I'm just the voice on this call. But the first thing is to say I cannot do any of this without the incredible group of people at Praxis that help every single day. And why do I push them? And they respond really positively. But the second and maybe even more important is that people who are here align on a principle. And I want to say to the patients, I see you. And that's why we are doing this for you. You know who you are, the people I really know with essential framework. This was for you, and this is for you today. Like thank you for keeping us going because like I -- every single morning, we're thinking as we criticize ourselves, as we think about what to do, the real motivation here is to help people.

I started in health care 30 years ago or so to help people. This is the pinnacle of my existence in health care to help millions of people. And I'm so happy to be here, but I couldn't have done without the phenomenal group of people inside the company and with the phenomenal group of people that donated themselves to help us execute this study pristinely. So, much appreciated, much more to come. I wish you a very bright rest of the week, and I'm sure we're going to be in touch.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and you may now disconnect.

Good afternoon, everyone. Thank you so much for joining our virtual fireside chat. My name is Yas. I'm excited to have Marcio firm Praxis here. We have a full hour for discussion. I know many of you are buried into earnings. So this morning has been very, very busy for all of you. Been very grateful that everybody is able to like during the fireside chat.

And again, housekeeping rule is the same. So if you have any questions during the fireside chat just utilize the Q&A box at the bottom of your Zoom and submit your questions, I'll make sure to direct them to Marcio.

Marcio, I think that maybe a good place to start off a sort of big picture, right? Before Mondays readout, we had the Phase I data. So we weren't really sure by looking at the Phase I data, how vormatrigine would differentiate. Now we've learned quite a bit around its differentiation with the data set so versus other therapies. So maybe walk us through what have you learned from the study?

And then question 2, also broad. What are some of the I guess, things and considerations that you think the Street has not appreciated into the data, and then we'll go really deep into that RADIANT?

Sounds good. I appreciate the invite, first and foremost, and I always nearly live in the future, Yas, but you just confirmed. I think it just good morning on every time zone in the U.S. So good morning, everyone, not afternoon.

So like if you take a step back, I just had a big picture of vormatrigine. What we are seeing and I guess what we continue to see carrying from great preclinical evidence to the PPR. So obviously, all the safety and pharmacology and everything preclinical and clinical seen so far is a drug that really can help patients with epilepsy a lot. And that was a promise until this week.

And I think that's quite important. And maybe on the -- I'm not sure if I say underappreciate it. I'm not sure if that is a need for appreciation as much as just people paying attention to on everything that's going on there on a world with very low and narrow attention spans is when we had the PPR data last year, there was a lot of clinical pressure to like say, what does that mean? What does that mean, right?

You might recall, we had some conversations. And we always, I would say, rightly so, said what we know is this growth in the brain, but we know that's doing something for the [iatrogenic] formation that's happening there. We're managing this. We're happy we can't really translate to what's going to happen when we treat a focal seizure patient or generalized patient.

A lot of like asks and pressure to try to translate. And I think we stay pretty serious about it because we really couldn't, right? That's where the science is despite the fact we have like 100% of the patients responding on that study.

You fast forward to the place we are today, the data set we really wanted to have for multiple reasons as the first data set, of course, is raised, where we treated a significant number of patients, refractory difficulty to treat, one could even argue the most difficult patients to treat, right? They want that actually gravitate towards studies like this. And it is undeniable how active the drug is, right? So transforming from a province to a drug is a big deal, in my view. And that's kind of what we have this week.

Now we can go one by one, as I'm sure you're going to go into the aspects of that and why we are so excited about it. But in summary, when we look into the actual markets, right, looking to not people like you and I or all investors on this call, but like the real people living with epilepsy, it is very, very clear, very short there. Number one, it is a massive market.

So the idea that, and as we go very quickly to the 0-sun game that while there is a drug or 2 drugs or 3 drugs that are going to solve the problem for epilepsy, I think it's a little bit delusional in Ferfetch. Now are there situations where you are like looking to the market in these lives that differently and you say there are like bigger winners throughout those lives, I think so and we can talk a lot about that.

But we do have 3 million, I'm rounding down patients and over 60% of them cannot tolerate our respond to the current treatment. I think we all would agree that there's a huge space here. Like looking to the history of epilepsy drug launches that were safe and efficacious and they all did really well.

Now imagine one of the profile vormatrigine and then you can imagine what it can really do. And I think that, that's why we're so excited, like we went through somewhat of a promise. Of course, we're excited about it to a lot more than a promise today with helping real patients with focal seizures, reduce their seizures or resolve their seizures as you've seen a good number of time.

Marcio, let's dig really deep into many elements of RADIANT and then we'll talk about POWER1 and POWER3. So let's start like just confirm the trial side. The RADIANT when you reported out, you said you had 61 patients as of July 25, and the total is going to be targeting 75, so -- and you're going to read that out in 4Q. So is that difference of 14 patients then generalized that we're going to get at? Or are we going to get in the next 4Q a combination of those?

No. A mix, I would say, we are pushing very hard for the generalized patients to be the majority of them. Of course, that is the data set that is missing here for us to complement. But there is still -- I think we're very transparent on the disclosure while talking about the patients that were screened, meaning they finished their screening.

There are, of course, patients in the screening and some of them are generalized, some of them are focal, smaller number in focal. And the patients that we dosed for more than a week, that's the 61 and between that and like multiple weeks. And then the patients has completed and that was the data set we [promised to Phase III] that we have here to discuss that was 37.

It is actually -- in a sense, it's a place of privilege rights to be with so many patients number one, interested and to being able to recruit in such a fast fashion, so many patients in this study, give us a lot of safety data, gives a lot of understanding of these patients, a lot of different background therapies and things like that.

So we feel for the stage of the program, running like multiple Phase IIIs in the next several months is a very good thing to have so much depth of data to learn what we can learn and you're doing a fair bit about, number one, how to recruit these patients, how to follow up and like incredible compliance to the seizure diary, for example, it's something super important, but it's never a given compliance to drug and everything else, management of AEs, as I'm sure we're going to talk about and it's a large number. This is not like 10, 15 patients as we had before. So that allows us to make a lot of extrapolation as well.

So I guess it's fair to say that when we get data in 4Q, it's going to include, obviously, generalized patients that we have not seen and maybe a few additional focal epilepsy patients that maybe had not finished 8 weeks at the time of the data cut of July 25?

Correct. Correct. You'll make a clarification here. All the difference between 37 and 61 are all focal. We only get focal numbers there. And we can expect a few more, 2 or 3 more or something like focal and then the rest generalized.

Okay. All right. Very helpful. Now I would like to spend some time on sort of walking through sort of exposure related to efficacy, safety and discontinuation because I think that's going to become really important as we think about this translation to the POWER1 study and POWER2. So I guess the first question is, can you confirm that the PK in patients was comparable in healthy volunteers?

Yes, beautiful thing. I love the fact you asked this because I don't think we discussed this enough. The number one thing we wanted to learn here, right, was exposure and safety and effectiveness. The exposure -- there were a number of questions we wanted answered. And I think we answered all of them so far. So the first one is exactly what you just asked. If the PK profile, outputs of PK comparable to our volunteers years or not.

But we know that patients with epilepsy in general, but talking about seizures, particularly, you have a lot of other drugs, a lot of co-morbid conditions, things just happen, right, on these patients. They're not clinical healthy as the healthy volunteers are on the study, and it's incredibly comparable. So we're very, very happy with that. It is very reliable as well in terms of predicting. So we want to first know like can I compared with what I have for our volunteers, but the second is can I extrapolate from that...

Yes. Before you go there is I want to kind of like walk through each of them step by step, okay? So we learned PK between healthy volunteers and patients was the same check. Second check is, can you confirm that the 30 mg dose group was linear in AUC and Cmax?

Yes, there was just like we had before, right? So we were expecting -- of course, we didn't have multiple doses here, but it was comparable to what we've seen with the previous most ascending dose for 30 and the exposure spread was similar as well, which makes us believe that the way the drug is [nothing makes more] similar, steady state reach more similar that there is nothing to believe here that the dynamic that you've seen before of linearity wouldn't be kept on this.

Okay. Next question is, would you say that the level of variability as comparable?

Yes, slightly comparable, yes. Surprisingly, right, you would expect a lot more variable here. So that is another very good metric.

Okay. So I guess, for example, so you previously disclosed that the coefficient of variables of 45 milligrams in healthy volunteers was 29%, you saw something very similar in focal epilepsy patients. So check. Okay, perfect. Now I know that now with this data, you guys are going to do any -- do extensive modeling, right, and think about sort of additional data over time. I guess the question that I want to know is like almost any exploratory analysis, you could look at quartile based on AUC. And then you look at the sort of seizure reduction, right? So you can actually think about treatment response to AUC based on quartile. So would you say it's fair to assume that the top quartile could actually generate 75% reduction. Like since it is linear, and you can divide it up, is that -- am I getting over myself as you think about that? Because that's going to be important when we think about the 40 mg dose group in POWER1?

I wouldn't agree more that that's quite important. Let me take a step back, right? So we collected intense PK on day 1 and on the end of study on day 56, and then trough levels throughout the study. So we make a number of predictions here, right? We use a PK model. It's been developed based on the healthy volunteer data and then we try to put this and so on and so forth, as you know well. So we asked a number of questions to that, like how is it not only AUC, as you just mentioned. But to jump into AUC, you have to believe it's an AUC-based phenomenon. It can be both ACU and Cmax or other actings. And I think that's a combination of both here.

And I can tell you that there is a dose response or concentration response because we did not dose here. That dose was just one for both Cmax and AUC in terms of response. If you split that in 4 similar groups, as you just mentioned, right, in quartiles, yes, the top group is better and better numerically. Now I always have to put a caveat right? This is not that small by study, but still -- we got to be careful once we start breaking down things into small and smaller groups. They will definitely expand from a situation at that. But it gave us confidence for 2 reasons, like without maybe getting off my skis and saying, oh, that's going to be a 7 or an 8 or 6 handle whatever it is on that number. I think there are a couple of parameters we wanted to make sure we're true for the dose of 40 to be selected for POWER2.

So the first one is, yes, the number has to be bigger, right, meaning there is a reason to go there from an efficacy perspective. But that alone wouldn't allow us to go there, right? Because it's all the side effect were concentrated there or there was like a very direct relationship, then we would have to pause as well and saying then we go there in the safety profile. But it's not the case, right?

So I think we have a lot more of a response in terms of efficacy than we have on safety from a concentration standpoint, possibly because there's a lot of other things influencing Phase II here and efficacy is really being influenced by the drug. So there might be why -- they might be right. It is amazing. I mean, is almost like what you always want, right? So you're giving more drugs, you get more effect, but you're not having any worse safety profile. And that was the base on why we believe that 40 would be adequate here in POWER2.

So yes, when you combine a time-based effect, which we haven't just done right? So it's causing concentration like independent of time, but you have both concentration, so it's time, so it's a longer period of time. We also see like depending over time of effect and going to 40, it would not be softer or correct for me to say I don't expect that margin effect there because it wouldn't be true. So that is what we are thinking.

Marcio, maybe you noted too, right, the PK and the exposure had no effect on safety. You just noted that. Did it have an impact on discontinuation rate?

Yes, it did not. Yes.

Okay.

Do you want me to check the box or...

Yes. No, no. I think -- no, because we have so many questions, but I want to kind of like team up in a way just as we think about it. So now that we're on the topic of discontinuation, let's just kind of close the loop as investors have asked a couple of things. One is when you think about the discontinuation rates that you reported of 23%, that 23% was based on the 61 that you got at the beginning of the study. Is that correct?

That's correct.

Okay. Okay. Second question was, was there a time by which the discontinuation occurred? And what that time cadence?

Vast majority of those patients discontinue in the first 3 weeks of treatment with a little bit more towards the first and second week there. It's interesting, yes, right? Like we are -- maybe to our faults, like we're saying like we're not happy with this. And it's not that we're not happy because the data is bad. Normally like people are not happy because it's bad, like it is actually very good from its continuation rate. Well, ideally, we wouldn't have any. But you've got to understand and we said this before, right? And I think those why find a little bit ironic that people bring it up as we haven't talked about this before. .

The setup of this study like attract patients that are a little bit more severe, that are a little bit more refractory. But also, they know their own drug. So they are more likely to attribute like anytime to drug and potentially discontinue. I think what we failed to maybe act a little bit faster was when we -- like we informed the physicians by the PIs and we train them and we reinforce the training with them. And I will say, it's never enough. And maybe if I'm going to call failure, maybe failure is like to just reinforce even further, because what we end up seeing was it was probably more related to certain sites than to the overall effect. Now we can't definitively say that, right? So I will keep running the studies.

But if the experience on POWER1 is of any information right now and it's blinded. And of course, we got to be careful with blinded data in general. But the overall rate is significantly smaller. And I think we can overlap, the fact that certain sites that have a little bit more discontinuation or not on POWER1 and they were the ones influencing if it was a generalizable phenomena, then we would be seeing like across the board in other sites as well.

So either the training or that we obviously always reinforce or the fact that there was maybe a little bit more PI dividend to some extent, and I'm not throwing anyone under the bus, right? No one patients to discontinue. It just sometimes happens, they might have unduly influenced the rates here.

And I'm not sure. So since you noted that the power discontinuation rate on a blinded basis is less than what you saw in RADIANT, can you remind us what you have said around what your assumptions were in discontinuation rate?

Yes. So we -- if you go back and look into the way we power this study, the -- all the data we had to work with was historical data, right? And you go through historical data on both drug and placebo throughout life. I'm going to call modern anti-seizure medication drugs. And you have like to you have like X-TOLE, you have like the [indiscernible] develop like 1.6 blocker and so on is looking to all of the data, which is publicly available.

And it always tends to be around 20%. You go across the board and you look into that and it's like a little bit higher for the most part, but I think we can say that the central tendency there is around probably 25%, but then we are like 20%. So that was the assumption to begin that we are on the actual protocol and how we determine the power for that study.

Of course, we believe that like with more intense management meaning like really just based like talking to patients, right? They talk to investigators together this morning. They're talking to all the time and they're like it's common sense to just call patients and check in on them in general, let alone clinical studies.

Sometimes it's just not done that we would and we still believe that in the future we're going to have like lower rates than that. But that's how it was defined in a sense, almost every study and every disease have a base rates and the base rate for epilepsy is around 20%.

Okay. Let's pause into a couple of clarification questions since we are on discontinuation. So I guess first question from a client is asking around what discontinuation in dose reduction rates were in the 30% of patients who were on background [indiscernible] patients versus the 70% that was not. So could you maybe talk about that?

Yes, absolutely. So if you look into those 30% or so, a little bit higher in the ongoing basis, [indiscernible], right? Those -- I think the way it was portrayed to me, I don't like talking about this, but I'm going to paraphrase, it's like the worst of the worst, right? So like we would threw everything at them in general. It was no difference than the overall.

And if we go and we look into 2 aspects of that, which is quite impressive in our view. One is to ask and I don't know what you hear from doctors, but when you go and pull the market and we ask which dose of [indiscernible], right? The most common number back and what claims data to the extent that [triangulation optimization] works here is around 200 milligrams per day. Those patients were around 300-plus per day. So they are way more prone to have all sorts of side effects and discontinuation, things like that. So it basically to say it's not had or anything like that is basically say, those patients who were really on the top of what they could tolerate the breakup plan. And the discontinuation was not any different, right, on this, which is, to me, it's quite positive.

I guess the one positive thing is that when we had done channel checks is that a lot of jobs docs don't really get comfortable to prescribe more than 200 mgs. So the fact that you had -- you just told me 3 -- like majority of them being on 300, really like highlight that these are really experienced docs that are part of the study because the normal doc would not feel comfortable to go there.

So like maybe another nuance here, I guess, just as you're walk talking through this is sort of the integrity of the study and the quality of the site. Yes. One more thing I want to drill down to is -- and you said in the passing as we were just having the conversation that the discontinuation rates were not -- they could have been run by few sites. Can you drill down? Because, I mean, did you get a chance to look at like what the distribution was because that's another maybe aspect to keep in mind?

Yes, we did. I think this is one of the first things on an ongoing basis. Our clinical team is quite on top of that and having conversations. And they also happen to be some of the first ones to patients. So no fault of their all in a sense, they are earning a little bit about this. And -- but that was somewhat of a concentration, I would say, the -- as numbers grow, you should keep asking like is this concentration real, right, as everything else we do. .

And I think now we can fairly confidently say, yes, there was somewhat of a concentration as we have a significant number of patients dosed across the program, which translates into a good thing, right? Because it is very hard when you have no idea where it is coming from. But it becomes while again, not necessarily positive overall to have anyone discontinued, but when you know it's coming from, like there are actions you can take. And I think the primary reaction here is just like a reminder, like consenting of the patient, reminding of what is the side effect. There's always going to be a random effect, right, on what happens. But I think we're trying to control the non-random effect like this one just described.

Another question that a lot of people are asking us, since majority of the discontinuations occurred between week 1 and week 3, how is that impacting the efficacy? Like how did you calculate total seizure reductions for the ones that you missed the data for, both for baseline end of treatment?

Yes, absolutely. So the most cautious way to calculate future rates, right, in epilepsy studies and maybe a little reminder there as well, I know it's obvious, but -- so we use an electronic diary where patients have to confirm their seizures are like they're off every single day. So we have like that and whether or not they took the drug as well, they confirm at a single day on the diary. .

So you have a number of days and a number of seizures, right? So you can greater rates there. And that is pretty much how everyone does. It's small variations here and there on the fringes. It does not really change the overall number at the end. So you would imagine that if a patient who discontinued earlier, they tend to be, number one, less opportunity to respond like as response depends over time.

And the second is that sometimes are not the best responders because like that's one of the factors on discontinuation. So that's kind of a double negative in a sense. And they are used, right? If that was the question behind the question, like this data is entirely used. So one could hypothesize while that's the proper way to analyze it, that reduce the effects, right? So when you reduce the number, you increase the effect hypothetically speaking.

Okay. Another if you could. How many total patients discontinued out of that 37 that you looked at?

Yes. So we're going to put the exact like numbers and like numbers at the IC [pulse] like 3 weeks or so. But you are similar in terms of the rates of discontinuation between 37 and the remaining that are in the 61. Numerically, a little bit more on the first 37.

Okay. That's helpful. And is it, I guess, fair to say that at the final analysis, 32 out of the 37 finished like 8 weeks of treatment then?

That would be a little bit better rates, right? So then you would make the other ones to -- no, a little bit smaller.

Okay. Got it. Okay. And then Matthew, would love to talk about -- I mean I think this picture here, if you look at other focal epilepsy studies, and I think it's in the appendix of your slide deck, comparing it to [ XEN1101 and SCN8 ] studies, they were between 23 to 27. So it's not really shocking that you ended up at 23. So that's like I think we get that. So I appreciate you answering a lot of color around it.

I guess another question that has come up is when you look at I guess one of the things is the total rate -- the reduction of seizure -- total seizure reduction was 56%. But if you look at the time curve when you look at week 1 through week 8, you really see actually consistency. And you did calculate your seizure reduction from baseline through week 8, you would have ended up with 70%. And I think even at week 5, you had 100% seizure election. So maybe kind of help us think about now that you learned this about your drug and POWER1 is going to be 8 weeks, like what do you predict to see by going longer and plus sort of -- and then remind us, what is the calculation of seizure reduction, I guess, to in POWER1 versus RADIANT?

Yes, absolutely. So we do see, right, I mentioned that on the PK discussion we had, both concentration response, which because there's some accumulation, there's a patent response to it as well, but a time-dependent response. Can we get in [indiscernible]? No. So they're both, and we can look into both. Maybe then too honest there, and so we really can't [indiscernible].

But we do see over time patients get better. I think the most obvious way to look into this is the spacing of the seizures, right? They get longer and longer in between and eventually, I think we all wish they go to 0 on the majority of the patients. So just by linearity alone, you would expect that to be 4 more weeks, that's the case for POWER1, that's the case for POWER2 as well and that the number would continue to reduce.

It wouldn't be farfetched if we're actually looking for our experience with vormatrigine and [indiscernible] every time we checked and vormatrigine are great data set to look into that because it's -- there's no discontinuation basically, right? So we are really looking to the same cohort of patients without much of a survivor bias, which sometimes the biggest problem on longitudinal cohorts is that you're really not looking to the same number on the long run or even a similar number on the long run.

So I think when you take that learning here as well and the learning we have for the vormatrigine, yes, it should. I'll go back to do we need it before people start creating patients and it's like, oh, it's not good if. No, very clearly no, do we want it, absolutely, right? Those are completely different things. Do we want to help this patient more? Do we want ourselves or someone else to free of epilepsy, absolutely. That's why we're doing what we do.

But then we need to appreciate as well that these results we have if replicated that we expect to replicate plus phenomenal to most patients. And yes, the expectation is that it's longer, it's more time to respond, it's more time to get to like levels of concentration that one would expect to be therapeutic and patients just have less seizures, the media number, of course, gets as smaller number, everyone gets happy and we move on. but the ultimate goal of this drug is to be widely used. And that is one step towards widely using, not the final step towards that.

Okay. Actually, I would love to kind of think about POWER1. One of the things that on Monday was a lot of analysts, including myself, asked around timing. But when I stepped back and started doing your math in my head and saying, okay, let's say you do finish enrollment today, right? And it's a 12-week study. So by the time that your data could be done, you will be sort of middle-ish of December, which then would mean the earliest, like would you want to put out data in the last 2 weeks of December, probably not great for anybody.

So I guess, can I say that -- is it fair to say that your hesitation to answer exactly pinpointing the timing of POWER1 is just that internal -- you know what, if everything goes perfect, and it could be things going to be done in mid-December and that's also not a good time. So it could slip in 1Q. Is that fair to say that is sort of what is keeping you to just say, yes, guys, the data is coming, I don't know. December, XYZ. So I guess that is what's driving your hesitation and fear.

Absolutely.

And I think you're going to announce enrollment completion, right? So then everybody can do that math. And you feel very comfortable that very much the enrollment completion is very near term, and you feel good about it, so nothing has changed. Yes.

So I'll -- since we're doing the math, let's go on last year as well. So there were a little bit shy of 20 sites that were contributing to RADIANT. And we see what happened, right? We gave them the opportunity to enroll more. They didn't enroll 1 or 2, like we're talking about having to tell people don't enroll more patients or RADIANT because I have too many.

It's not a different problem with POWER. It's the same problem. I'm calling -- the fact that I'm calling that a problem so oxymoronic, right, because it's really not an issue in terms of enrollment whatsoever. It is just a very long process, right, for these patients. it's like for 2, 8 weeks, they screening. And so any patient that entered the period is like it takes a very long time. I think we learned a lot about how to screen this patients efficiently and the site has been phenomenal on helping with that, but it still takes several weeks in that -- that's the uncertainty I would call versus fear on the final date of all of this.

Okay. So just a confirmation question from a client coming in. Can you confirm as you enrolled more than 50% of POWER1 patients?

All right. I think can get started now. Good afternoon, everyone, and thanks for joining us for our virtual fireside chat with Marcio De'Souza, CEO of Praxis Precision Medicine.

Before we begin, I need to read our safe harbor statement. This call has been arranged by Truist Securities Research for use by institutional investors as defined under FINRA rules. If you're not an institutional investor, please disconnect at this time, and please see our website for our equity research library and the required disclosures. If you have any questions?

Can you hear me Marcio?

I can hear you.

If you have any questions you like asset management, just e-mail me at [email protected], and I'd be more than happy to ask that for you.

And I hope you can hear me now, Joon.

I can hear you. Let me just ask because one of my associates that they can't hear me. Okay. I think they can hear me now.

Awesome.

All right. So -- all right. Good. Thank you. Thank you, everyone, for telling me that you can hear me. We have some audio. So let me just quickly read the disclaimer. This call has been arranged by Truist Securities Research for institutional investors. And if you're not as defined on the FINRA rules, if you're not an institutional investor, please disconnect at this time and see our website for the required disclosures at the Truist Research Library. And if you have any questions, e-mail me at joon.lee.truist.com, and I'll be more than happy to ask them for you.

So Marcio, thanks for making the time. You had a busy day yesterday and today.

Does have that.

Yes. That's a little bit. And you top line data from the open-label trial of RADIANT evaluating vormatrigine for focal epilepsy. I want to dig into the patient disposition the efficacy that you top line and the tolerability and background therapy and upcoming data at IEC and POWER1, 2 and 3. But you start off with maybe a 5-minute recap of what you shared yesterday.

Yes, absolutely. I appreciate being here today after like a great data that we presented on RADIANT yesterday. Maybe we start talking a little bit about the market itself, right, because maybe that's where this always started and then how RADIANT and POWER1, 2 and 3 would play a role here. We know -- I think we all know that how large the epilepsy market is like about 3 million, 3.5 million depending on how we look into the number in the U.S., of course, proportionately more outside of the U.S. Many drugs have been attempted, many drugs are approved to treat epilepsy patients. But unfortunately, I would say on one side, that is really not a solution right now, not a drug or a set of drugs that address the majority of these patients or even the minority of these patients. So on that side, fairly unfortunate, there's a lot of opportunities there.

On the other side, fairly fortunate, right? Because what we know is, you can come in on to this market and as we're looking for vormatrigine, make a real impact with a drug and it's by no stretch of imagination, the only drug or the only set of drugs like you had 3 other epilepsy drugs for focal epilepsy. It would be interesting to develop all of them in a sense because the markets really can accommodate a number of drugs. And I think that is a very interesting motivation because what I see a lot going on in conversations that we have way less with the neurologists treating these patients, but a lot more with people like us and conversations like this. Is this impression that there's a race for the last few patients, right? And while maybe one day, that's going to be the case, and it's going to be like one way to cure epilepsy. I think right now, we're really trying to get better and better as these drugs and treating more and more of those patients. So in that regard, incredibly happy on making a step forward.

I think the second incredibly positive thing about it yesterday is it's a little bit of a water like divider for us, right, moments or shared moments where we were very bullish about everything that happened before yesterday before vormatrigine in terms of the PPR results of the preclinical data or the Phase I studies. But we always said, until yesterday, I would still have said that, we need that data in focal patients to really be able to, like say, this is a drug that is highly effective in for concept seizures. And I think we are now at the moment that we can turn that page towards really saying that quite confidently.

Now from this point on, then it's how to bring this drug to patients in the broader markets. Looking to the profile of this drug is one that really sets itself to keep moving lower and lower on the adoption. I think everyone starts. One could argue rightly so. I'm not sure if I agree with that on these hyper-refractory patients. They are important, but they are a fraction of the market. They are a small fraction of the market. They're incredibly valuable from a revenue perspective, but there's still a small part of the market. but then moving lower and lower would be ideal. If you go from an external reference and then I'm going to bring an internal reference by looking to the human epilepsy project, one that focus on focal onset seizures. That was the 2 of the focal and generalized. There are 2 major conclusions there that I think are super interesting. They have many, many conclusions, but I'm going to focus on 2 of them. One is, there is no doubt that modulating sudden channels is the most effective way of treating focal onset seizures that's from that set-up obligation for that large study that was on is still ongoing. And the second is the cycle of ASMs is not the best thing for these patients. When you put those things together, it's quite nice to have vormatrigine to be able to add to that, to replace many of those drugs right now and to move towards really eventually as our vision, and we're going to talk about that on POWER3 to really be the drug of choice and doing needs to get there to be a multibillion-dollar drug now as we don't need to show many things that people oftentimes ask us to. But that is the vision, and that's the path towards that position.

And then the second piece, and I'm going to get out of the subbox here is the fact that we completely replicated that with our own data, right? We run a fairly large claims analysis about 0.5 million or so patients in the U.S. and it maps almost one to one in terms of like the use of drugs, what they stay the longest are on solvent channel blockers, what we see patients like cycling through like about 60% or so the patients at a second drug and then a third drug and a fourth drug, and we see them cycling a lot. So it creates a nice market dynamic from a revenue perspective that you can always add another drug doesn't really matter in a sense, but a huge opportunity for a drug like vormatrigine. So we're going to talk about the results, but I wanted to set up a little bit to the market opportunities that is in front of us.

Thank you, Marc for that. And we will use some slides that you shared yesterday to go through some of the details of the results. But to your point, the centrality of sodium channel modulation as the cornerstone of epilepsy management was I mean, 81% of the patients in your had backout therapy sodium channel blocker and actually managed to show pretty remarkable seizure reduction even on top of that. I don't know how your remain with modulated sodium channel could even work on top of an existing sodium channel blocker because the receptor must be already occupied. So that -- that's for another conversation, right, because -- but that was important. And I mean -- so I think I don't want to like run this too much, but are you going to need POWER3 to register? Or is that something that you might after submission with...

Yes. No, not at all. But I do want to take a little bit of a segue from what you just said, right? The priority, if you think about like "rationally," we're going to pretend to rational animals as humans, like adding same mechanism, right? People talk about orthogonal versus non-orthogonal mechanisms and stuff like that, it wouldn't make sense, right, that you actually have so much more efficacy out of that. But take a step back and ask the questions like, if this thing, I'm going to cover vormatrigine a thing for a second, that we are putting on top of other things that are similar are not really dissimilar. It's not really different. Why would you show, let's say, from a more basic level. So we see that as yet another proof point on how different this drug is. And therefore, its ability to continue to grow the market and to replace certain drugs and to add to other drugs because at the end of the day, it's not going to be a magic or silver bullets. This thing there is space for a lot of people and that there's a space for vormatrrigine for certain.

Got it. All right. That's -- I'm going to share a screen so we can actually discuss with some slides. This is a slide from yesterday's data presentation that describes the patient disposition and the RADIANT. 99 patients were screened, of which 61 were dosed to date, and you presented data from 37 patients yesterday. Now how many -- of the 61 patients that were dosed and remaining 24, how many of those are still focal epilepsy and how many are generalized epilepsy?

Yes. So -- and I'll be the first one to say you probably could have being a little bit more clear here the here. So here is the chance. So the slide is entirely about focal onset seizures, focal epilepsy, right? So the way I'm going to walk from left to right because I think it's going to be a little bit simpler. When we set up to do this, we're like -- we're going to give about 35 or so patients, right, 50 times 0.7. And we saw accounting, right, 1, 2, 3, 37. That's how that 37 was defined, was the 37 completers at the time that we did the data cut off on the 25th of July. So that is the first 37 now. Between the time that we actually said to the site, we're pretty close like we're getting we're getting there to the 35. And when we actually stop completely recruiting for focal and I'm going to go back to generalize, there are significantly more patients on that process. Now the process takes anywhere between 28 days and 56 days to screen these patients, so you see that it can just not sometimes stop or running train. And that's on the periods that were these other patients that have been started dose. So it's anywhere between a little bit over a week to like about 4, 5 weeks that these patients would be dosed. So it was a mix of exposures, but pretty significant exposures for the other patients here on the difference between 61 and 37. That's why we included that on the safety because we thought it was very important of those at that point in time, 99 had completed the screening. And what do we expect is like within those and a few more that are not included here for generalized we would have like a general update at AES later in the year, and that is the box on the left mall side of this slide. where we expect with the focal like 61, 62, 63, whatever the final number is there. And the difference between that and 75, that's where would be the overall. And the difference is the generalized patients, where the primary generalized patients. So I think the bottom line here is we're not only delivering what we said we was for focal, but really show the incredible interest for this drug and for this study. And just the ability to recruit, I think that is one of the many urban agents out there is just how hard those patients are and how difficult today is to recruit patients. And of course, it's not easy and requires a lot of attention, require attention to quality. But it is completely doable like as we are showing here.

No. I mean so just to nail down on the details here. by -- in fourth quarter, you'll have data maybe at AES on about 35 patients that will include the 37 patients top line yesterday with longer follow-up beyond 8 weeks. And there may be more focal epilepsy patients included in the AES presentation maybe. And then...

There will be. Yes.

There will be, yes. And then generalized. So what's the breakdown of generalized versus focal when it's all said and done?

So the intent here is to present all, let's call, 75 patients at AES, of those a little bit over 60 are going to be focal onset seizures and the difference there, let's call 15 for the sake of the argument right now should be generalized.

And so basically, is it fair to assume that the 61 patients that were dosed to date, that's all FOS?

That are generalized patients, those that are not included on the 61. So all those 61 that are here are generalized -- focal, sorry.

61 patients dosed that are local, but they were not included because they haven't crossed an 8-week follow-up?

Correct. That is the only reason.

I see. So there were 37 that had 8 weeks' worth of dosing data and then 24-ish that did not -- that have less than 8 weeks.

So anywhere between 1 week and about 5 weeks. .

Got you. Got you. And then -- and then subsequent to that, you started adding generalized epilepsy patients, that's up 75.

And we're well on the way there.

That's very clear. Thank you for that. All right. And then, let's get into the sort of the demographics, 81% as we discussed, were on sodium channel blocker, 65 were on -- is it SynGAP [indiscernible].

Yes, yes, that's right. [indiscernible], yes.

[indiscernible] modulators. Is this typical of -- does this represent like typical patients in the epilepsy, focal epilepsy, what's the kind of drug they're on?

Yes, absolutely. On the -- we showed one slide on our claims work here, but it's actually a very extensive analysis, not only of like the type of drugs they're in, the duration they're in, how they cycle, what's the decision triggers and stuff like that. So I can comment a little bit about the U.S. market in detail there. So this is fairly typical, right, of the market. And normally, the vast majority of patients in the U.S. start with [indiscernible] or with [indiscernible] and the vast majority of them fail, right? That drug has the lowest response rates of like any drug that is widely used here. So it's not unexpected in a sense. It's a very easy drug to be given to patients, and that's why it starts there. One of the reasons why it starts there and then they move normally to a sodium channel blocker on that case and they go back to other things, they come back. the ad sodium channel blocker. So the steady state, if I may call that way, end up being something like this, a makeup that is similar to this.

I'm not an expert on epilepsy, but just being a biotech analyst, looking at other trials, if I were designing a trial, I would have avoided patients who were on sodium channel blocker because it seems to be done. Like you're working -- you've got a blocker, you're a modulator, okay, that's a new one. You work at the sodium channel and you have patients already on sodium channel. So I would have avoided them and actually try to like not enroll these as an inclusion criteria, but you haven't done that, and this is actually where the demographics.

Yes. I think once upon a time, maybe some people still believe that there was this idea that people were responsive to a mechanism, right? And I think for some patients, it might be true for certain mechanisms. But generally, you're trying to stop decision. And I think there is one thing that we can say quite pretty confidently. You cannot have one if you properly modulates sodium channels, right? They're fundamental for initiation propagation of seizures in general. What we know as well, right? Yes, they are on all those things. but it's not working, not completely at least, right? You're looking to the median seizure there the bono like, this is very high. So this is fairly refractory in terms of refractory seizures, right, not only to a given treatment. And most of the time -- and we made this in another slide, this point, but maybe just to make a little bit more than one way, there is a lot of stacking here. And the stacking of different drugs is not necessarily one would call rationale, right? They're very much like empirically driven at that point in time or if the patient in front of them. And oftentimes, it is driven by whatever they can do at the moment.

So when you look into a drug that actually you are very confident can stop seizures, as you've seen on the results, I'm sure you're going to go there next. You kind of have to ignore this noise about what is in the background and ask like, can we do that? Can we actually -- and of course, 10 steps ahead that is the easiest one to replace, right? Like if you're thinking about POWER3, for example, like this is a very obvious replacement, there is not a lot of other markets or a lot of drugs in development that I know of that the easy replacement is 80% of the markets and the drug is going to be better, like I think everyone here in this call knows how to do math, you can just imagine like what kind of markets that can be.

All right. I'm getting e-mail questions, but I'll save all that for the very end because -- and we need to move fast. But just one quick point I want to ask here. Were patients on in this slide, were there patients who were on more than 1 sodium channel blocker?

Absolutely. Yes. There were patients in 2 sodium channel blockers, a fair bit actually about half of all the patients sodium channel blockers were in 2. And there are even a situation patients were on 3 sodium channel blockers. And then we have, obviously, adding the vormatrigine on top of that.

Okay. I mean -- but -- if something works, I mean, if you have one sodium channel blocker that works, is there a point of having other sodium channel blockers or sort of targeting drugs on board?

Yes, I would say absolutely. I think when you talk to like the physicians who are prescribing these drugs, of course, those are real patients. There are real physicians behind us. They are not done, right? They are actively trying to help these patients. They're very smart actually. There are limitations on all these other drugs, right? Like we look into vormatrigine, there's certain limitations from an immunological or immune response perspective. There is so much you can do with that or lacosamides that are other limitations or even like older generation drugs like carbomezapine or CARB, all of them, I think they are trying to do the best with the tools they have at hand. Those tools are suboptimal, but they are really well intended. They are really trying to help these patients. And for the most part, they are helping these patients. So that is -- it's not to say that there's not a better way to do it, but definitely, they're all trying to do the best here.

And one more point. So and we will get to this towards the end, but you talk about trying to take off drugs like to avoid AEs, how do you go about picking -- like let's say the patient is on 3 drugs, like one, Keppra, sodium channel blocker or GABA, which one do you take off? And how do it seems like a very imprecise?

Yes. And we can get there. Maybe we'll move a little bit to talk about the -- that's okay. since you said you want to manage the time, I'm going to help you manage the time.

All right. I mean, look, this is -- there's no controversy here. I mean you saw this 50% reduction in 60% of the patients, and you see a median 56.3%. And again, you have response improving over time? And 22% Cedar freedom, that's really the impressive aspect about the drug, which is at the last month. You had like Cedar Freedom even on top of Synovo being 30% of patients. Anyway, but before I move on, like, have you -- are there any like particular response based -- have you stratified response based on background therapy, did this work better in patients not on sodium channel blocker or what sort of a with or with us how does that efficacy look?

Yes. So I'll go down in a minute. I just want to make 2 points about the previous slides, right? So one, when you look into this, these are all patients are included here on both panels, right? When you look into the overall median like 56.3%. This is like considering every single patient in the study, it does not remove any of the discontinuations that I'm sure are going to look into that. I think we got questions before. It's like when you look into the overall media, this number looks bigger, right? Because the point for all of that and what's happening, obviously, we always get a little bit impacted by discontinuations and things like that. The same thing with the more than 50% response on the right-hand side, this is the entire cohort like every single patient counter their response. And you look into those 2 together, together with what you're looking to the baseline characteristics before, this is very hard, right? These are very hard results to be to be seen on these 3 of the population. So I just wanted to make that point because I think it's quite important to put in context. The patients are capturing their seizures every single day. And then when you put this all together and having such a robust reduction here, it's very, very clear. The drug and is very clear to derisk of the program as we move forward.

But maybe to answer your question about the background, which is a few cuts that we thought was interesting to explain that, right? So we're seeing this very high response rates, we look into patients without any seizures at the last 28 days, we're like asking the question, okay, what is driving this? What is driving this high? And there are a few things that are kind of obvious questions. And if we could go to the next slide, it seems like you have the entire deck there.

So the first question one can ask and has been debated a lot and less, what is the influence of where they start, right? So they come into this study, they are treated with a lot of antisera medications. They have this disease oftentimes for decades, they failed tons of other drugs before and they are seizing a lot. Is the drug working on people who are seizing very little? We're not working at all on the ones that are seizing a lot at baseline, of course, on the 28 days of baseline or is there is a general impact. And I don't think this is very controversial here, there's always a little bit more numerically response on the lower patients, right, just by definition. I think it's easy to understand. But it is a question, right? Like what happens when you split this group in the middle. Now one finds the right like perfect time points, like it's not like if you pick like adherence like a splits a group on that like when you split by the median, it's nice to see the day split like being so homogeneous.

If you go to the next one, I think that's why it answers part of your questions, actually. One thing priority, we did not expect, Joon, was the amount of patients actually being on a stable dose high dose, right, to give you a little bit of a view. I think when you actually ask a lot of physicians when you look into the claims data, the dose up and all making as is normally between 200 to 300 milligrams per day. Very few people go higher than that. Here, the mean was actually 300. It had a significant portion of patients with more than 300, 400, even 450 milligrams per day. This is a very unique opportunities that we had because no one so far developed like a drug that had a result after some became so important in the market. And we know how effective the drug is right? So one could -- if you asked me this before, I was like, what is your expectation for how well this is going to work on top of [indiscernible], I probably have said not that high. This drug is very effective. There's probably a lot of -- there is not a lot of residual like ability to help there. But if you flip to the next one, and then I'm really going to answer your question since I've been lingering here on answering your question. And you got the 3 most common like ASM use here, right, like sodium channel blockers in general, and that might be 2, might be 3, of course, includes [indiscernible] as well, [indiscernible] and [indiscernible], which is a very prevalent one is on this cohort and tenant by itself. So it's very effective across the board. One could argue is like if you're going to remove something a priority what would you remove, of course, this the discussion to be held with API and with the [indiscernible].

Isn't that an easy question here because cenobamate is a risk he hits up. So wouldn't you remove [indiscernible] first? Or I don't know. Isn't that?

I think that is a fairly reasonable way to think about that. But as you can see, there are multiple ways, but it may be the most fundamental questions, do you actually need to remove something? If you're talking about POWER2, and the answer is probably not always or most of the time, not as -- then when you go to POWER3, then yes, we're looking for switch to monotherapy. So we're going to have to reduce things and it might be an order of the reduction. .

Got it. Marcio, before we move on, I just want to better understand. So there were some patients who discontinued, but these data represent all like 37 patients who for us were included in the analysis. Now 23% discontinued which is not out of there. We can talk about that. Why don't we actually go there? So this is a paper from Xenon's publication where in the 25 milligrams that they're taking forward 114 were enrolled, of which 26 did not complete for whatever reason, about 23% discontinued. So it's not out of the ordinary. And they also have to deal with some importation of data that we're missing based on the discontinuations. I don't know, and this is what they showed. How do look similar to what you show here in terms of the fluctuations here in the slide? So there is definitely some noise there, but how was the missing data imputed from the patients who discontinued.

Yes. So epilepsy has this interesting. If you read slightly statistical plans and the reviews, they say there's no imputation, right? But technically, it's not exactly right because you use the rates of the patients at a given point in time to use as the terminal rates or to -- and that is equivalent to impairing the average. So -- and basically, the way it works is, let's say, a patient had 2 weeks and they had whatever 10 seizures, right? So we're going to do like 14 days on that week, then seizures calculate a rate per day multiplied by 28 on day 1 is pretty as and that is the -- basically the rates and you compare with the previous 28 days. And that's how you calculate and then you carry that forward. I think some people say that's a last observation carries really not, right? It's not the last time we've observed is the overall rates going forward. So all of that is included. It tends to penalize the median. It is here. As you can see, it's probably the best way to look into the overall impact, but what we know from treating physicians, they are not treating the discontinued patients, they are 3 the continued patients. So there's always an interest on the overall impacts, which is what you have in this slide, but also what is impacting general when I keep treating these patients.

But Marcio, because the patients gained the most seizure reduction in the first week or 2, as shown here, if you actually have a patient who discontinued at weeks 3 or 4, and you're using -- applying the rate of senior reduction of week 1 and 2 out to week 8 or so, wouldn't that actually favors -- unfairly favor greater seizure reduction.

Yes, I was, right? So what you are seeing here is the median per week. So in that given week who is having the response and the median for that week, not the overall. So you have on any given week, people who respond really well, people that don't respond so well right -- if those are the ones who drop as it tends to be, right you actually don't influence as much on the weekly basis, but we're doing a lot on the final.

It depends on what drops out. And is it fair to assume that people who just continue are -- they're self-selecting in a way, they drop off because it doesn't work as well rather than dropping it really well?

Yes. And that is -- and it should have been obvious in the chart but maybe did a poor job on the scale. There is a fairly substantial reduction between the first periods in the second period, right? By being first period, I compare is the first month on drug in the second month on drug. So in a sense, the worst thing is actually towards the end to up for discontinuation to happen are the best thing for the conical imputation is actually the worst thing towards the beginning.

And is it fair to assume that -- how you analyze the data here in terms of imputation of discontinuation, patient data from discontinued patients are no different than how the [indiscernible]?

Exactly the identical.

So it's an industry standard?

Yes.

Nothing suspicious there. Okay. Good. Good enough. The other thing I want to touch on is, let's say -- yes, I think that we want to end up spending quite a bit of time here. And I definitely want to leave 5 comments at the end for questions and also to go over POWER1 and 2 and 3. But 23 patients -- 23% discontinued, which again, is not out of the ordinary versus [indiscernible] trial and [indiscernible] trial in hindsight. But you also mentioned in both this like discontinuation of reducing the background medication should improve adherence or how are you going to do this. And I know that you're -- maybe you're encouraging investigators to say, you know what, some of the background medications you don't need or not working [indiscernible] and just -- how is that going to work in POWER1, 2 and 3? In a blinded trial, investigators don't know if the patient is honored not all be much. So we were hesitant to peel off drugs?

No, absolutely fair. A couple of points there, even before we jump into the POWER1, 2 and 3 studies, right? You're right, like 23% is I would say, similar in general to what they see in other epilepsy studies, nothing to be alarmed there. We do think we can do better, right? And I think that's why we're talking about that. do we need to do better? Maybe that's the first question. And I think we always have to try to do better for patients, but let's take that aside for a second. And the answer is no, right? So if that was it. This is going to be a competitive drug. This is going to be a drug that's going to get a very significant market share in a competitive setting and can move towards actually being a dominant player when you remove sodium channel blockers or other drugs in the market. So like if nothing else, all things being equal, that is totally fine. I think the observation we wanted to give here because that option was on the table for the investigators. They're like to. And some of them taking some didn't, right? So we're saying, one they did talk. There are a couple of things that are from a learning perspective. This is a learning study, right? We said from the beginning, we want to learn a number of things. The very first learning as does the efficacy deteriorates. And that is the most important question. I don't get as in business slides, but you reduce the dose of the background. If the background, what was keeping things together, for these patients. And I can say quite definitively, no. Those patients responded really well. So that is you can entirely attribute that response to vormatrigine and that's quite important, right, as we move the drug forward, then the implementation on POWER1, and it might be a little bit too late on our POWER1 nfor an implementation. I'll talk about that in a second. But it doesn't seem to be needed either, right? So a couple of things from a POWER1 perspective, like going pretty well, we're not done yet, but we're pretty happy with where we are. And what you've seen so far if we use like the worst case for placebo, like meaning no one discontinued and -- or the best case in the worst case for drug and like the majority, not seeing the levels of discontinuation you're seeing here. So I think we feel that even the training that was reimplemented and really the counseling of the patients and a lot of that was sufficient for -- to minimize some of those because the majority of the AEs were really fairly quick transient, mild in nature.

So is that a big deal when we have like, again, in the grand scheme of things are fairly low, and I know 59% does not look low, but it's comparatively fairly low. Treatment emerging AEs and we can actually manage. I don't think that we are in a territory that it is an issue here. So we are starting with this is not a problem and then we are moving to can we make it better. And I think that that's quite important as we discuss these aspects, right? We're trying to make a problem out of something, it's not a problem. And -- but just maybe because we said we can do better. But our intent is always to do better. That's why we spend time here.

What percentage of the 23% discontinuation was due to AEs or some other reason?

Yes. So we were very good about following up with the patients and we think that scatters and understanding was there any associated wet, right? And one could argue to our faults because when patients just continue and you go and ask them afterwards like I wanted to discontinue and you record that as patient choice, you avoid the terminology of the , but you first say you had an AE, just continue. You normally record AE. So the vast majority of the patients, said has an AE and discontinue. And that's what I believe happens in most of these studies, but that's the case here. .

I mean, I guess you did some of the work for us and in comparing the drugs -- yes, I mean, look, 59% or was it 52% PAE drug-related is. It doesn't roll that back relative to other drugs...

Well, I'm going to take an issue with that. Like if 30% or 40% less patients are having treatment emerging is that is a lot better. We can talk about being comparatively everywhere else, but I'll take a problem here because it's not only the rates once they have it, that's how sometimes are calculated, but are they having treatment emerging as at all? And 60 versus 90 versus 85 is our very different numbers. You're talking about a significant proportion of patients not experiencing rate margin. And for the vision of the drug, for the get to the markets, the competitive get a good share might not be so important. But in the long run, it is quite important for where we want this drug to be.

And I mean, so when you unveiled the plans for POWER3 yesterday for the first company in an effort to study vormatrigine as a standalone or monotherapy, right? Same thing standalone monotherapy, one they get washed out of the background therapy. People thought I mean you could have a barren a bullish interpretation of this, right? The bullish is that you want to study this as a monotherapy potentially positioning it as a more frontline therapy ahead of other sodium channel blockers. The fairest argument is that there must be some drug-drug interaction that you're trying to avoid as a monotherapy. When did you when did you decide on the POWER3, tell us a little bit of the history and conversations that went on with the investigators and all in decision to do POWER3?

Yes, I love the conspiracy theories, right? Ben slides, that is like the GGI profile for these drugs. And by the way, we combine the drug with all these orders, like that. There is no one is trying to avoid the GGI here on the very concept of GGI. That has nothing to do with that. But moving to what it has to do with, right? If you think about the markets or go back to the market with epilepsy, right? Getting off the gates, we're going to add another drug for refractory patients, right? POWER1 and POWER2 are going to position us to do that. The market is $1 billion to $2 billion. And if there are 5 other drugs that are all going to be $1 billion to $5 billion to $2 billion, like that is not a winner take all market, right? That is like a market that people cycle, there are several patients there. And one could argue that is enough and sufficient and great in a win to actually be in a position to derisk that position. But when we take a step back and ask like where does this drug can go then we believe strongly that it can keep moving lower in the adoption curve. And the best way to show that is to actually remove some of those drugs now do we need to remove it. I think we answered that before, as now as a condition to be successful in the market. But should we remove it or should we as debt and make sure we can remove it. So we can move faster towards first line and then actually replace all the drugs that vision then eventually and have a market that, hopefully, at one point, is going to be 2 or 3 drugs, that are used in general instead of like this, in a sense, madness that happens with all these drugs right now. So this is a conversion to monotherapy right or patients got reduced sequentially.

To answer your question, what do you take first. They're going to be 1 or 2. You can choose the 1 or the 2 and you're going to take a denture going to introduce vormatrigine at the same time. for these patients with the expectation that they're not going to lose ground and they're going to gain response. Many studies like this were done before. I think some of them are fairly old and some of them use like subclinical dose of other drugs. I think those are all deemed to be unethical to be run because like or using subclinical dose for other therapies and things like that. Some of them use like scape rates, during that conversion and so on. I think we're all still having some debates on how to do it. I think our strong preference is really to try to keep these patients as stable as possible, of course, as safe as possible. Some of those escape rates in the past were very aggressive, not towards the patient like 2 or 3x increase in seizures. We don't think that, that's fair to patients at this day and age. But we're going to get back to the design of this once we finalize when we start this next year. Maybe the other part to be excited is actually the POWER2, one that we are starting clinical now by the end of this quarter, where we had a key question for RADIANT. Going back to the things that we intended to answer if RADIANT was 30 milligrams effective dose. Can we dose that off the gates like without any titration without any adjustments there? And I think we checked those boxes, right? Or should all agree react those boxes. But in a secondary question there was, do we have a reasonable evidence that if we give more drug on board, that the efficacy could be better, one, so from a response rate perspective versus like exposure. And then on the other side, is the side effect profile worse if we increase the drug because if they are, then you got to be very careful. But if they are not, right, if the efficacy is higher in the side effect profile is equal or lower, then you know it's almost you have to go there. because like you have like a base quite strong, solid foundation of the 30, but you can explore these new highs with the 40 and that's how we picked the 40 here basically just got the rationale for you there. Now on POWER2, we can more aggressively I'll call, they were aggressively now like with aggression, but with being incisive here to reduce the background drugs by a bit by 20% or so in the first week. So our levels are fairly safe but can actually keep all these patients responding better and managing them better. And that answer your other question, how do you manage on POWER2. POWER1, too late, but we're pretty confident that all the measures already in place or able to manage, we be able to -- were able to manage, and I think in POWER2 is going to be even more effective.

Going back to POWER1. What's -- I got a lot of questions around the timing of POWER1. In some slides, you say you will finalize the POWER1 in 4Q. On other slides, I think you've said you'll report in second half of the year. What's the status there?

Yes. So last mile for POWER1, all right? And when you are the last mile of something, you always like to start asking the question is like, okay, when does it end to get like the actual race, and you got like marked up the time and that's when last patient last visits. But then like when do you get the matte and that requires a lot of other stuff to happen. And when you look into that, it is the end of the year. And being the end of the year with [indiscernible] prudence to just like give that at the end of the year view right now, and that's the disclosure we have right now, there is no, I know there were some conspiracy theories about that as well. and there is nothing there. It's just like a fast-moving study. Every fast-moving study has thousands of pies that are moving and no or very confident it's like we're very happy with the number of cases that are being referred every single day. to sites on the medical review, on the quality of the patients, like on everything else, just like we were on RADIANT. And here we go, not only did he run the 35 plus that we said we would. But may more there. Almost every single patient between 35 and the 60 or your single RADIANT would qualify for POWER1. So we got to ask the question, like we got to be fairly confident to be able to keep them on RADIANT when you actually do need that instead of like actually funneling them to POWER1.

So fair to assume that the baseline characteristics in POWER1 will be very similar to what we saw in RADIANT?

Very, very similar. Yes.

All right. And the last question before I take some of the investor questions, I see -- EIC on August 31. What do you think will be -- what are you going to share or to the extent you get there, what will it be?

Yes, will tell a little bit. So of course, a little bit more about everything we talk today, like that, obviously, a scientific meeting. There is a lot more -- a little bit of the details here and there. We do have a few new analysis that we conducted like, for example, one that we're very excited about is by seizure type. So really showing that, as you know, there are 4 major seizure types that we actually measure as we go through 3 of them get part of the endpoint. One of them is normally not part of the endpoints, but really like showing that, I think it's quite interesting. It's quite interesting in general, but it's incredibly interesting from the impact you're having like that across the board that our type is like what about the ones that are like focal to bilateral with generalized type of seizures and without giving too much under saying we're excited about that as well. And a few other things here and there. Of course, we need to be careful scientifically and otherwise where I had a purpose. AES has a different one. We submitted the full or the expectation to have the full data sets to AES over the weekend, and that's where we expect to be the entire wrap up for all the patients.

Yes. All right. I don't even know where to start with the questions. what evidence do you have that going to 40 is going to lead to better efficacy? What kind of internal what exposure data do you have that supports going to 40 milligrams?

Yes. So again, going back several months ago when people would ask, why are we doing radiance. Then one thing we said is conducting intense PK sampling is easier in a study that you know patients are on drug. It's easier to ask for a patient to stay like a full day, taking samples in another line study. So that was one. And with that, we can not only understand better the PK of the drug itself in patients, mother volunteers. And second, we can use that data to fit to a PK modeling to do a lot of exposure response to explore covariant matrices and things like that. So starting with the first one. The very first question is the exposure different, right, in how volunteers in patients with epilepsy. It answers indirectly and directly your question, is there a significant CDI hidden here in plant sites that we actually haven't detected that is influencing the PK of this drug. And I can tell you quite categorically, the answer is no. The -- the exposures are very, very comparable between our volunteers. And that is very important, very important because, of course, we know the drug is behaving well. .

But second is we have safety on 45 in how volunteers, and we can borrow that experience to predict safety. And as you said, about POWER2 and how we select that. And then the second question is the one I answered before, but just to reiterate, when you actually use now the exposure response parts help this modeling. And you asked the question, are higher exposures, and I would say preliminarily because for people familiar with these models, that it takes a while for them to be finalized preliminarily, I can say the base is positive, meaning you give more drug, you see more response for some patients, it's not something exaggerated. It's not something by model, what you see like no response and then high response, but there is some hints there that we could benefit, number one, and you're not harming #2, which is quite important. So when we put that all together and the fact that the FDA told us they would kind of like for us to explore higher doses. I think that's deal.

You had a pre-Phase III meeting with the FDA and you brought up the POWER2 dosing up to 40 and they were okay?

Yes. So we had an interaction with the agency where we basically expose the entire program and we like. This is what we're trying to accomplish here with this drug, right? POWER1, POWER2 ranging from exposure to GGI like Phase I studies, you name it. And I think the feedback at that point in time, we're under the impression that they would want us to go lower to like 10 milligrams. And you might -- if you go back to previous disclosures, you even added that 10 milligrams, like we're so convinced they're going to tell us to go there. They were like, "Oh, maybe we should go there." And I think the feedback was quite different. So like if you really believe on the profile that we were describing to us, right? It might be warrant to actually go higher. And I think we took that to heart, and here on a point that all scientific boxes are tracked towards going to 40 milligrams because we can expect potentially, of course, we need to run the experiments a higher yes then, like POWER1 should be very solid. We expect POWER1 should be very solid efficacy and safety. But if POWER2 replicates that efficacy on the 20 and 30 milligrams and actually gets higher on 40 gives a lot of flexibility for physicians to use this drug on how to treat their patients.

And there were on average 2 background medications and ASMs. How many -- is there data on how many they failed?

Yes, very substantial number of ASMs they failed. The -- I would say the worst case here was 22 or 23 ASMs patients in general, like 5, 6, 7, then was not uncommon on this data set. In general, we would see 4 or 5 ASMs being failed out like that. And that is even the ones that I would argue the patients recall and the physicians have on their records. You tend to have a limit for like 10 years of medical records in most patients in the U.S. and the majority of the patients have more than 10 years of epilepsy treatments.

Got it. And then someone was asking, you mentioned something about the interim dropout rate in POWER1 being lower than that in RADIANT. What does it look like on a blind basis so far in terms of dropouts and discontinuations in POWER1?

Always tricky to talk about ongoing studies. So I'll please take with a grain of salt. But I think what we are seeing so far is lower. And and it can be for many reasons, right? And it's hard to speculate. I think one of them is if for open label study as RADIANT was or is, I guess, still ongoing for those other patients. have something like I have a headache, I'm going to call you attribute immediately to the drug and you're like, I'm not sure I want to stay with this. I think when you are in a double-blind study, and you have had days before and dizziness before and some lunch before because these patients lived with all these other drugs, it's not so easily attributable. And then, so there might be one.

I think the other one is there were somewhat of our relationship with a few sites would they have higher dropout rates than others. It so happens that they were not side had a lot more patients to offer to clinical studies. So they're not really contributing as much or contributed as much for POWER1 proportionally which allows for actually the sites. So we didn't have any. We had bigger to be a bigger contributor. And then the last one is training. Price is just like going back and on the constantly on the ICF and everything else being better. So I can't possibly disentangle which one of those parameters actually is influencing the most certainly, all of them are.

And how many of the 37 patients actually had their background ASMs reduced?

So 6 of those patients had their background reduce. None of them got completely removed the 8 weeks period, which is a question I got as well the other or yesterday. The -- it was a reduction at the majority of the time is like 30% to 50%, the reduction they had those was completely investigator-driven, right? They would think it's a good idea and they would reduce it.

Okay. There are so many question.

Pick the tough ones.

Somebody is asking, should we still expect essential tremor update in the fall.

Oh gosh, okay. So you really managed to get that one. Yes. So we just updated the disclosure yesterday to talk about like we finalized since we went there and seems there is some general interest. I'll always start by saying we ask everyone not to attribute any value to a central number right now to take it out of their models. Having said that, we have completed all the explorations. We wanted to complete the modeling and so on, on the blinded data for Study 1, and Study 2. We believe that we found like some small chains that would quite significantly impact the result of the analysis, but not the integrity of the analysis, which is always what we are aiming for. Here we've made those changes to the [indiscernible] plan. In the process of doing that, we enrolled a few more patients. So we wanted to get the studies to rolling before we actually finalized documents. That's all said and done. So in the past, we said the fall because it's really like the kind of the very end of September to like the beginning of October. And someone joked with me yesterday. It goes all the way to November that we're just talking about and like that's now what you're talking about is really that interface between the end of September, beginning of October.

Great. And then do you have Xenon's trial allows [indiscernible] as a background therapy or not?

Yes. very unclear by the public protocols, I believe so. I would imagine so it would be interesting, if not, in the most American way, I can say the word interesting. But the -- I would imagine like [indiscernible] prescriptions grew about fold since the last study was conducted by then. So there is a lot of those sites that you end up going to have a lot of [indiscernible], as you've seen, was over 30% in our study. So all the imagine is the same on layers and anyone else studies. .

I think we were past the hour, and we asked a lot of questions the questions keep coming in, maybe I can ask this one last question. What was the seizure free first 28 days?

I'm not going anywhere. Yes. So the cure -- and of course, this is stuff that we are holding for our IC and AES. But I'll give a little hand, right? The seizure free rate trial based study, both first 20 entire study, last 20 was all high double digits. So that is nothing we...

Cedar Freedom rate.

Yes.

Interesting. All right. The questions that keep coming in. But I think we can also do another one of these and -- but it's very interesting data. I think seizure freedom rates efficacy on top of sodium channel blockers, multiple sometimes said a lot about the drug's profile. It's just about designing a [indiscernible] that shows of the true power of this format. So we look forward to the presentation on August 31 and further disclosures and 4Q.

Likewise. Thank you so much for the time.

Absolutely. Thanks, everyone, for joining. Goodbye.

Thank you. Bye.

Good day, and welcome to the Praxis Precision Medicine's RADIANT Top Line Results and Second Quarter 2025 Financial Results Conference Call. [Operator Instructions] As a reminder, this call may be recorded.

I would now like to turn the call over to Dan Ferry of LifeSci Advisors. Please go ahead.

Good morning, and welcome to the Praxis Precision Medicine's RADIANT Top Line Results and Second Quarter 2025 Financial Results Conference. This call is being webcast live and can be accessed on the Investors section of the Praxis website at www.praxismedicines.com.

Please note 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 time lines and financial projections. While these forward-looking statements represent Praxis' views as of today, they 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 on 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.

Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis; Tim Kelly, Chief Financial Officer; and Steve Petrou, Chief Scientific Officer. After our prepared remarks, there will be a brief question-and-answer session.

With that, it's my pleasure to turn the call over to Marcio. Marcio?

Good morning, everyone, and welcome to the RADIANT's top line results presentation. We're incredibly excited to share this [indiscernible] disease results with all of you. Before we begin, I would like to note that today's presentations contain forward-looking statements. For complete disclosures, please refer to our latest SEC filings. Praxis is in an incredible position to bring innovative drugs to patients with CNS disorders. We have 4 late-stage assets, 1 of which we are discussing here today, and we expect 5 clinical [ readouts ] within the next year. There is no small feat. This progress is powered by our 2 robust platforms, enabling current developments and future CNS drug innovation. Our cash runway extends into 2028, supporting our ambitious clinical agenda.

Today, we'll discuss the RADIANT results for [indiscernible]. But it's worth taking a few moments to remind everyone of the rich [indiscernible] pipeline we have with multiple readouts coming out in the next several quarters, which will enable Praxis to stay at the forefront of CNS drug development.

Focal epilepsy a very serious medical condition impacting about 3 million U.S. patients. Contrary to common belief, most of the patients are now doing well. Over 60% of those patients require multiple antiseizure medications, highlighting the inadequacy of existing therapies. Patients need effective, tolerable, fast-acting and durable treatments to avoid a constant ASM cycling, and we believe vormatrigine can deliver on that.

Starting with today's results, vormatrigine is showing best-in-disease efficacy in the RADIANT study. That should be enough to be excited. We should not minimize the further differentiation of vormatrigine with current and in development therapies being the only drug to combine,once daily administration, fast action, no food effect ideal tolerability and no meaningful drug-drug interactions, which importantly do not interfere with common contraceptive agent.

Before I hand over the call to Steve to discuss the details of the RADIANT study results, I want to take a step back and talk about execution. We have executed the RADIANT study exceptionally well, initially setting an enrollment target of 35 patients with focal epilepsy and 15 have generalized epilepsy. The strong demand for focal, even after we announced the closing of the enrollment to the site, demonstrate the effectiveness of our recruitment capabilities. The same engine is already at play for the POWER1 and soon to be for the POWER2 and POWER3 studies.

We have so far completed screening of 99 patients in those 61 as of July 25. We expected to complete the study in the near future with approximately 75 patients dosed. Today, we will review data from 37 focal patients who completed [ VA ] study for efficacy so far. We also review the safety for the overall [indiscernible] the 61 patients who have been dosed.

We present more details from this initial cohort of patients at the upcoming International Epilepsy Conference in Lisbon later this month. The full study results are expected to be presented during the American Epilepsy Society Conference later in the year.

Let me now hand over the call to Steve to discuss the results. Steve?

Thanks, Marcio. Let me walk you through the design of the RADIANT study. We began with a 28-day observation period during which patients stayed on their existing antiseizure medications while we monitor seizure activity. Following that, participants received 30 milligrams of vormatrigine once daily for 8 weeks. An optional 2-week safety follow-up was also available at the end of the treatment phase. We're proud to have enrolled a representative sample of the [indiscernible] epilepsy population here in the U.S., predominantly female with a high baseline seizure burden. The median monthly seizure count was 12 and most participants were on multiple antiseizure medications.

Looking ahead, we expect the population in our upcoming POWER1 study to closely reflect what we've seen here in RADIANT. That alignment gives us a strong foundation and confidence in how we're approaching the next phase of development.

Now let's turn to the part of that we're most excited about, the results. Vormatrigine delivered a truly remarkable performance in the RADIANT study. We observed a median seizure reduction of over 56%. And importantly, that effect came on quickly and was sustained throughout the treatment period. Even more compelling, 60% of patients achieved at least a 50% reduction in seizures. That's 1 of the highest responder rates we've seen in recent epilepsy trials, and it speaks to the potential impact vormatrigine could have for this community.

What's especially striking is how quickly these responses emerged and how they continue to improve over time. By just week 1 54% of patients had already responded. That number climbed to 67% by week 8, showing a clear and encouraging trend of improvement. Even more notable, over 22% of patients, more than 1 were completely seizure-free during the second month of treatment. That kind of outcome not only underscores womacroGenc's potential but also sets the stage for what we hope to see in the longer 12-week Power 1 and POWER 2 studies. Looking more closely at the data, for Macrogen efficacy held strong across all patient subgroups, regardless of baseline seizure burden. We specifically analyzed outcomes by splitting patients at the median baseline seizure frequency to explore whether those with a higher or lower seizure loads responded differently. As you can see in the figure, the drug performed consistently well across both groups. That kind of robust and uniform response is a strong signal of reliability in a heterogeneous epilepsy population. Taking a step back, it's important to remember what treatments these patients were already receiving when they entered the study. The bar in Radiant was especially high. This was the first epilepsy study launched and reported in the U.S. following widespread adoption of [indiscernible]. In fact, 30% of RADIANT participants were already [indiscernible] meaning vormatrigine had to demonstrate efficacy on top of an already aggressive background regimen. That context makes the results even more compelling.

When we looked at response rates based on the most commonly used background ASMs, the results are consistently strong. Patients showed excellent responses, whether they were on 1 or more sodium channel blockers, SV2A modulators or even sonobumate. This level of consistency in both efficacy and tolerability and across different treatment backgrounds speaks to vormatrogene's versatility. It reinforces the idea that this is a therapy with broad applicability, not limited by the complexity of background regimens. -- safety and tolerability. Firmatrogene demonstrated a favorable overall profile. Most adverse events were mild to moderate and tended to resolve over time. We did observe a 23% discontinuation rate, which, in many cases, was linked to a lack of background ASM dose adjustment despite protocol guidance. Importantly,

most of the patients are not doing well. Over 60% of those in 6 instances where investigators proactively reduced background ASMs, both adverse events and discontinuations were avoided entirely. We see this not as a safety signal related to vormatrigine itself but rather a manageable interaction dynamic that can be addressed with appropriate background therapy management. I'll close by saying how proud we are to share these results today. RADIANT was a high bar study in a complex and underserved patient papulation really supports vormatrigine potential to make a real difference for people living with refractory epilepsy.

With that, I'll now hand the call back to Marcio..

I'm sure you are as excited as I am about the strength of the RADIANT data Steve just reviewed. As we move forward, we must remember that 1 of the key motivations to conduct RADIANT was to better inform the final design of POWER2. In that regard, one of the key aspects Steve did not discuss was the preliminary modeling for dosing and efficacy.

We have concluded that it would be beneficial to add a dose arm of 40 milligrams to the POWER2 study, bringing to life the potential of even greater efficacy. We also intend to be more deliberate in our instruction to [indiscernible] dose reduce the background ASM for even better management of patients.

Another incredibly interesting piece of inflationary learns in the RADIANT study is the reported positive impact in moods observed in patients. With that in mind, we decided to include a depression and mood endpoints to the power show design.

We're ready to start rolling out POWER2, and it goes without saying that the full force of the practice recruitment engine would be at it. The final design of POWER2 enroll approximately 400 refractory epilepsy patients, testing vormatrigine dose of 20, 30 or 40 milligrams against placebo over 12 weeks. The enrollment is expected to complete in 2026. .

I want to now focus the next few minutes into a very important and often neglected part of drug development in play. As you can see here, we're presenting some data from a very large U.S. client patients with focal epilepsy conducted by practice, which covers almost 0.5 million patients worth of data.

The message is very clear. The majority of the patients are not doing okay, and virtually 2/3 of them fail their first-line treatment. And after that, very improvised layering of multiple agents begin. This is not good for patients or the health care system. Clearly, there's a critical need for simpler, more effective treatments vormatrigine, ones that combine the fast acting mechanism with minimum restrictions and high effectiveness.

With that in mind, we'll be launching POWER3, which aims to establish vormatrigine as stand-alone therapy, enrolling role refractory plastic patients transitioning off currently ASM. This study leveraged historical understanding benchmarks and safety matters to protect the integrity of the patients and the results of it.

And we plan to initiate POWER3 in early 2026. To wrap up the call about vormatrigine, it's incredibly exciting to be the point where we can confidently say it has emerged as best-in-disease ASM distinguished by rapid seizure reduction, favorable safety, ease of use and sustained effectiveness across diverse patient group.

The RADIANT results significantly bolster our confidence in the ongoing and upcoming studies for vormatrigine. Before we move to Q&A, and reminding that today's results is about celebrating vormatrigine, I want to emphasize that practice remains deeply committed to revolutionize epilepsy treatments from common focal epilepsy to rare conditions. I'm sure we have seen the fantastic news of relutrigine being granted breakthrough designation here in the U.S. which will allow us to move even faster towards registration in patients with SCN2A and SCN8A.

Lastly, we extend our sincere thanks to our investigators, patients, site staff and practice team for their contribution to the success of the epilepsy program in overall. We now open the call to Q&A. Operator?

[Operator Instructions] Our first question comes from Yasmeen Rahimi with Piper Sandler.

Team, congrats really to the outstanding data, both in treatment response as well as seizure free, especially at the majority of the patients are on background therapy. I guess the first question is, have you looked in terms of the background therapies, were you able to look at if there was a difference in response rate if they were on different products. That's sort of question number one. And then a question for number 2 is just given the incredible execution into Radian and that and you provide a color around POWER2 reading out in -- POWER2 finishing in the back half of 2026, could you maybe help us understand sort of, I think we get the question a lot, what were sort of the nuggets that leads you to execute really strongly through the study? And then the timing of POWER1, I think a lot of -- it sounded like you're on track to finish POWER1 at year-end, but if you could just reconfirm guidance around timing of POWER1, that would be very helpful.

Thanks, Yas, like incredibly enthusiastic, right, as we come out here, when you look into Pocola background in general I think your question is exactly on the specifics. The first question on the specifics for the background. If you look across Keppra or any of the -- as and our team, right? We sell incredibly robust effects on sudden general blockers in general, some patients were in 1, some patients were on 2 like you wouldn't expect much of an effect there. I think that was some of these ceptism before, and we're seeing incredibly robust effect as well with over 57% of patients having a response -- but maybe the most striking result on that same slide is patients on this study over 30% of them were on 300 milligrams or even more, sometimes 400, 450 of cenobamate, this was not our mildly treated like a run-of-the-mill eblapsy patient. And on those patients, we're seeing over 55% of response. So if there is any doubt on the placements in terms of refractory, I think that should be no more. We did talk as well on what we believe to be the proper way for this drug to be used is really moving towards first therapy and first line. And that's why we're starting the POWER3 study, but I'm sure you can discuss that soon.

So going back to your question, right? We set up to recruit a smaller group of patients than we end up recruiting. That should be a big check mark on our ability to recruit this population that as you've seen on the demographics slide, as SR classical refractory seizing a lot multi treated patient population in the United States and in Europe. So I'm pretty happy with that. Not happy for the patients on being treated with those drugs but happy on the fact that we can recruit them well, it's already happening on Power1, the acceleration we did in our corporate release 10-Q, which should be filed right now, and you can refer to like reinforce the guidance that we previously gave on finalizing POWER1 this year. POWER2 is not off the ground yet. So 1 should always be careful on making predictions of studies that have not started, but based on our engine, particularly here in the U.S., we are really able to get high-quality sites and to help the sites with their own recruitment efforts with our own recruitment efforts to get more patients, we believe more patients in a site is a good thing because then they have more experience, the qualities higher, the overall operations went smoother. So that is going incredibly well. So we're going to transfer that enthusiasm towards POWER2, and pretty soon in the future POWER3 as well. So it's on and all -- it's not only a phenomenal result as we see for patients today. But in general, it brings us a step closer are much closer to completing POWER1 and to getting POWER3 and getting that registrational. It's particularly sad as others struggle here to recruit on the same population and 1 must ask why. But on our case, we are incredibly happy of our execution and our team's focus on getting these patients on these studies.

Our next question comes from Ritu Baral with TD Cowen.

Congratulations on this on this really, really good data. I've gotten a bunch of questions this morning. Just being driven by this 22% seizure free rate and the sort of large percentage of patients that responded very rapidly. Marcio and Steve, what do you think is driving this increase in efficacy on all these measures. Even after steady-state plasma is achieved new patients -- and is your -- do you have any exposure response analysis done, which is contributing to the 20-milligram dose that you now plan on including in POWER2? And then I've got just a quick housekeeping follow-up.

Yes. The -- so we do have the exposures, and I would say that the raw exposures are already quite well processed and the preliminary exposure response well underway as well. So I'll make a couple of comments about that, and then I'll hand over to Steve to talk about why we are -- we were expecting and we are seeing this phenomenal results. So we do see steady state being reached quite quickly here between the first and the second week of treatment. .

As you've seen on the slides, off the gate to get very good results, it did [indiscernible] quite considerably. We thought the most scientifically relevant way to present was actually fitting the lowest to the charts because we know epilepsy is not a weekly process, right? Like the patients don't sense otherwise, we'll observe them for a week and then just for a week or 2 afterwards. And it's the overall month. I think the matter here. But we do see less -- I think the overall concept is that less seizures leads to last seizures. So we see this deepening over time, which bodes incredibly well for POWER1, which is 12 weeks long. And POWER2 is going to be 12 weeks long as well on that regard. The 20-milligram dose that we are using for the first 6 weeks of POWER is rising to the range where you are seeing this incredible efficacy, clearly in the 30 as well. But what you've seen is a potential for a fairly significantly higher when you go to the much higher side of the exposure of these patients to get an even bigger results here.

Now that we need it, not like this is the highest seizure reduction ever seen on an epilepsy study. Not that we need anymore, but I think these patients do deserve more and they're going to drive that. And that's why we added the 40-milligram [indiscernible]. It's good to be stepping in into POWER2, expecting all 3 dose to be quite effective and giving this flexibility for the patients. But maybe Steve can talk about why we think the [indiscernible] is granted.

Just speaks to the issue you raised, Marci, about fuel seizures causing fuel seizures. And the same thing -- the old saying in epilepsy is sees beget seizures, and that's a process of really resetting the activity level of a neuron. That's a molecular process that takes time to occur. -- conversely, when you give an agent like relutigenevematrogene, you immediately decrease activity, and that's actually starting to reset the level of neuronal activity. So that process takes time to unwind as it took time to wind up -- so we just think it's really the opposite corral of increasing seizures as a patient first presents. And there's well-known physiological mechanisms, homeostatic plasticity at that are known to underlie this phenomenon.

Super helpful. And then, Marcio, you knew this was coming. The upcoming POWER1 data, you mentioned you would finish women and have data by end of year. Is there any more granularity that you can give us around where enrollment currently stands? And will you announce completion of enrollment for that study?

Yes, we probably will announce the completion. And I would say, at this point today is the day to celebrate RADIANT. But yes, I could see this coming. I appreciate your processing with that. The enrollment is incredibly strong. I just had a call this morning with most investigators and enthusiasm of everyone that is on POWER1 is really great to see. I know it was in these lines, and I reinforce it, but the rate -- 1 of the things on rates that we are not expecting was really this overwhelming feedback from patients and investigators on their improvements in moods on their ability to call better with their day. And I think investigators like that a lot as well, and that is certainly helping with even more patients being funneled towards this study versus other things going on out there. .

Our next question comes from Joon Lee with Truist Securities.

Congrats on the beta for taking our question. Can you elaborate a little bit more on this discontinuation rates in the Radian and how that was imputed into the seizure reduction data, if at all? And also for the forthcoming Power on, would it be fair to assume that placebo rates will be lower than those reported for cenobamate and drug given the more refractory population in POWER1.

So why we are -- we think we can do better on the discontinuation, right? Like if you look into competitively our other studies, it's fairly similar. As I'm sure you've already done the comparison in overall. So not but completely satisfied are there yet because we've seen what happens when investigators like actually follow the bills they had on the protocol, it doesn't happen, right? Or it happens at a variable rate. And I think that's why we're going to see moving forward. Having talked with some of them already over the weekend and so on, I think some regrets they would then have removed some of the drug. So not as much on the impact to your question on the ability to reduce seizure, but just that is a lot on top of these patients, and I think that that's what is leading primarily here for patients don't want to stay because that's what [indiscernible] come out as well, right? When you when you are in the open-label setting, it's certainly more reports of side effects in general and easier to discontinue. So I'm not completely surprised a little bit higher than we expected, but it's still lower than cenobamate competitive to other drugs in the market with lower efficacy. .

And you mentioned what we should be expecting for POWER1. I agree on -- in general, what you're seeing in this patient population are 2 things, right? So 1 is the background, as you mentioned, very difficult, very refractory in general and then the second is really the quality of the sites, the quality of the patients are coming in. The stability of these patients on their seizures beforehand. So I think when you get like higher number of patients per site higher quality of assessment, good level of stability in terms of the seizures beforehand. That all contributes to lower potential placebo rates.

Our next question comes from Douglas Tsao with H.C. Wainwright.

Congrats on the data. I guess as a starting point, in terms of the added effect of the increasing efficacy that we see over time, that was something that we saw with the Lucene as well. And I'm just curious, the 2 molecules are similar in many respects. Do you think that, that is a function of sort of how they interact with the sodium channel uniquely that you sort of get this detindling effect, which sort of I think Steve sort of talked to I think in response to Ritu's question, and then I have a follow on.

[ ]

Yes, maybe just to further what I said before, Doug, yes, that's very specific and different to how any other molecule interacts with the sodium channel, their biophysical profile. And we think that's got a lot to do with this effect because they target the activity more than the target normal function. They target the epileptic activity. I think that profile leads to this rapid and then it's growing because we're having such good acute efficacy that encourages this longer-term efficacy to grow over time. So very much associated with our physical character.

Okay. Great. And I guess on the side effect profile, I'm just curious Marcio or to the extent that you've been able to sort of detangle the effect that some of these side effects were or AEs were related to vormatrogene versus the background therapy -- and as you look to the power studies, sort of thinking about enabling some sort of reduction in dosing in background ASMs, which obviously probably contribute to many of the side effects experienced by patients.

Yes. So absolutely right. But maybe before they all ground us on the table on our Slide 23, -- the for antigen treatment emerging as with over 20% lower than any other drug out there, 20% less patients. But if you're talking about any other therapeutic area, this is like 100 miles from anything else. On CNS related, it's about 20% as well. So we're already at other like universe when it comes to these other drugs that are unfortunately in the background, right? So we this intent. These other things are doing. But what we know because we run the experiment is it gets reduced or removes when the background drugs are reduced, which ultimately is what these patients do, right, in what the physicians there. So we see that it's incredibly positive not only for patients continuing RADIANT since we have significant more now and for open-label extension as well. But for the POWER1 and POWER2 and potentially POWER3 I studies as well. So yes, I think the trajectory, while we should ground on the numbers and be happy about being best-in-class and here in best-in-disease that is a space to get better. That's why we're moving forward.

Okay. And if I can, 1 follow-up. I'm just curious on the mood benefits that you saw. I'm just curious, is that based on sort of anecdotal feedback? Or was there any kind of sort of inventory on emotional taken?

Yes. So you will start systematically reported by sites. But unfortunately, we have not designed an instrument to collect that from the very beginning. And that's where we are incorporating the power to design. It's not completely unexpected, right? I think there's other drugs in this class that have approval for like bipolar, for example, like lamotrigine, but they just can't be used probably because of the other issues, including like the allergic reactions to the drug. So not -- again, not completely than expected, but you all a very welcome comments that we got across the board from investigators. .

Our next question comes from Yatin Juneja with Guggenheim.

Let me add my congratulations. Very nice results, again, congratulations to the team. So a couple for me. So the first 1 is, could you talk about the kinetics of responses in the sense that are you seeing improvement in efficacy over time for most patients. And then when you do a 12-week study, you'd probably get more benefit. And the reason I ask is because I couldn't really figure out from the chart that you have, are you seeing sort of deepening of this efficacy throughout the period. So that's first.

Second 1 is what should be the read-through to generalized data that you will have for the same asset? What should be the expectation there? And then finally, on the safety, which I'll ask, I mean you should be very comfortable with the safety, especially the call it ability if you are going with the 40-milligram in the future studies. Those are the 2 questions.

On the kinetics of the response it is very clear, if we thought it would be this ingenuous just get a straight line there to fit like a linear. But if that was the case, and you can do yourself since the data, you would see a very significant Japan between the first month and the second month, which we expect to continue as we treat this patient further. So for Power One, the translation should be even deeper response there. Of course, going to have to wait for that study to read out, but that is the expectation based on the data we have. And that is kind of the read-through that was the second part of your question. We're looking to safety as we're very comfortable going to 40 milligrams. We really see this association being a lot more related to the time and type of management by the investigators than the drug itself. And we do see, as I mentioned, 1 of the previous questions, on the higher end of the exposure response we see even further efficacy response or tipping. So when you combine that, we form with another month of treatment, we should expect significantly better results here, not once again, not that it's needed, right? This is already the best results in epilepsy study. .

Our next question comes from Ami Fadia. I'm sorry, Ami left the queue. 1 moment, please. Our next question comes from David Hoang with Deutsche Bank.

Congrats on the data. So I just wanted to ask about some of these other work that you mentioned you're doing with the program here in terms of I guess, mood endpoint and port looking at a role for monotherapy. How do you envision some of these other endpoints and additional studies here could -- are you looking, I guess, to enhance the label or get some label differentiation versus what's currently available and what else is in the pipeline?

So on the moods benefits, right, I mentioned a couple of minutes back, that is an expectation that a drug that reduces the seizures make these patients feel like more leave from the hyperexcitable activity and with this mechanism that is known for -- in a specific way to improve load in general, to be positive. So we are looking for adding that as an endpoint, potentially a label claim, of course, pace on the results there. On the POWER3, switch to monotherapy study, I think that's a game changer, right? We haven't really had a drug for many, many years that is able to move to those 100% of the patients there at the beginning versus the 30% on the bottom. So when you're talking about the refractory -- hyper refractory patients like fourth or fifth line, as we show on the chart on this slide, we're talking about a $2 billion to $3 billion market opportunity there. When you move up to the first line, second line, we're talking about several folds that potential. So from a market opportunity perspective, it makes a lot of sense, number one. But for a drug profile is the only drug that makes sense. Well, let me remind everyone that Keppra, which is now the the drug that people use at showed an efficacy of like 30%, basically no seizure freedom and with very similar pharmacological properties and overall toxicological properties or for matrogene. So we're not talking about a high bar to replace there. We're just talking about the fact that no other drug we're able to. So that is expected to get off the ground pretty soon and to if completed before the NDA submission beyond the NDA, potential NDA, if not to be a quick add-on to the label there. .

Our next question comes from Ami Fadia with Needham & Company.

Congratulations on this really strong and impressive data. I wanted to sort of better understand the discontinuation rates. If the physicians were allowed to discontinue any background therapies, why did they not do that? And for the 6 or so patients where they were discontinued, was there any change? Or can you kind of talk about the change in the efficacy as well as the safety adverse events that were noted after the background therapies are removed. And then maybe a related question on -- what additional data do you think you need to generate perhaps in an open label portion to convince physicians to switch out patients from their existing background therapies and then move patients through vormatrigine?

Yes, absolutely. So Ami, on why people haven't done something, it's going to be kind of speculation on a bit on my end, right? But it informed the speculation since we had that conversation. And I'll refer to 1 conversation, for example, I had with an investigator in the last few days, who was a little bit slow to start reducing. And I think his point to us was, and to me, particularly. Well, we're so used about keep adding and just doing nothing and then cycling these patients on that the reaction time for some of them. This is a big key opinion leader, someone is very important for the space and the number of patients in the trial. And then when you realize was the first few patients that was not the case and that for the following ones. -- was able to and worked really well. So I think it's a timing thing and really people learning other with the drug at the end of the day, that's why we did the study as well. On the ones that did removed. I think we mentioned that on the slide as well, it's not only resolved the As, right? That was -- efficacy is not impacted like at all. in the long run, efficacy is actually better on those patients, but we should always be careful to talk about individual patient results on things like this. So that's why we give us -- it is not that reducing the background made the patients worse, which is the general concern, right? One would have and linking to your question about POWER3, I think that would be concerning if that was the case, but it's not the case at all. .

In a sense, I think what we established is that the background therapy is not doing anything but causing side effects and vormatrigine getting these patients better -- so a monotherapy studies switch to monotherapy makes a lot of sense. We pulled a number of physicians on the last few days as they are under CDA with us -- and I think that is an incredible enthusiasm for Power 3 because they really believe on vormatrigine, but they didn't have an opportunity to do something like that before with any other drug. So not hearing a lot of concerns. Of course, there are ways to do it. There are dynamics on this study, but not really an overall in concerned about it.

Our next question comes from Jay Olson with Oppenheimer.

Congrats on the pet results and thanks for providing the update since you mentioned the observation that seizures beget seizures, -- is there a way to show that for vormatrigine could potentially have a disease-modifying benefit? .

Yes. Thanks, Jake. I would, again, are I'll ask Steve to comment here as well that that's what we're already seeing when we have the direct benefit of seizure control and then the indirect benefit of patients just feeling generally better better moods, better relationship with the site and with their own families and so on. And ultimately, I think what we are looking for here is to change the plan as we know it. .

Take a look at our slides when we're looking to, people keep saying 30% of patients are refractory that's 1 of the biggest PS that anyone can say in clay. -- is like over 60% of those patients are on several therapies, right? And that is just not acceptable, like those things are not benign as we know, so they affect the well-being of patients as well. When you remove that, get an effective drug that not only reduce procedures but improve their overall well-being and particularly moods, as we discussed, I think we have an opportunity to really change everything here, but maybe Steve can talk about it.

And I think it's back to that earlier point about SC's beginning, Cess is the disease but it's a new set point for the brain, where a higher level of activity, a higher threshold for triggering seats. It becomes the new normal. And this reduction over time in sizes that we saw and that we talked about earlier, is a sign that we're reversing that process. So -- and that can be exactly what you're talking about, disease modification. So -- and then all the attended things that happen. If you've got a brain that hyperexcitable mood disturbances and other things emerge and the fact that we saw changes in other domains. I think it's very encouraging that we are really tackling some fundamental issues what epilepsy is. And we see this across rare, severe epilepsies this there common epilepsies like focal as well. But it is a disorder of seizures and excitability and resetting that set point is key to disease modification and improvement across multiple areas.

And maybe if I could just ask 1 follow-on. Do these impressive Radiant results give you any hint that vormatrigine potentially could have benefit in DE .

In theory, yes, right? I think we can with -- the good news is the reletting is quite strongly set for GEs and Emerald is off the ground that you might have seen on our corporate release a couple of minutes ago, enrolling patients. We do expect to have very strong enrollment and results there as well on the GE side. That are things, features that are important for GE patients that we might not be able to fulfill with like a solid form that is like vormatrigine. But in theory, right, these drugs are dampening hyperexcitability on a hyperexcitable neuron that is seizing a lot, so yes, there is no reason to believe not, but we're really looking straight on and quite focused for lamotrigine for these and vormatrigine for adults epilepsy. .

Our next question comes from Brian Skorney with Baird.

Let me extend my congratulations as well on the nice data. I like the chart on Slide 13, you have breaking out the efficacy by back rammed, so I'm just wondering in that vein, if kind of pushing on some of the color on the safety profile. Do you have a similar slide deck to kind of look at how safety breaks stand by background. ASMs, Obviously, some of these are pretty sedatives. So I wonder if it's just a driving force behind some of the dies and some ones that could be discombobulated from drug. And just to confirm, are these all focal onset patients in this data set? Or are there any grand mal patients here?

Yes. So, Brian, this is all focal and stat seizures. We're going to have the primary channelized later in the year at AS here, so maybe get that out the way -- as you can see on both the demographics stable and on that slide, right, this number sums to much more than 100% in terms of the overall. So patients were in a multitude of antiseizure medications, which makes that analysis of what is actually the culprit a lot harder. But I think what you can say is we look into not only the ASM their end with the total levels in their blood, right? And when you look into that, it is very clear that a significant proportion of those patients are on toxic concentrations, meaning higher than the maximum allowed concentration in the United States. And you do see some more out of an association on those cases. So people are not monitoring from therapeutic drug monitoring perspective to frequently and [ have ] these patients. I would argue they should and obviously, they are a lot more prone to have side effects. And 1 of the reasons why we're being a lot more proactive on the reduction of the dose of the background. .

Our next question comes from Rudy Li with Chardan.

Congrats again on the strong results. Just a quick follow-up to the question regarding the background therapy. So can you provide additional color on the potential impact touching of current background therapies. I'm just curious how that change your enrollment criteria connecting the right patients for the pivotal trials? And what kind of additional data you think will be necessary to support its use in combination with other sodium China bankers in practice?

Yes. Rudy, I think what you've seen here is the only real sample of how patients are treated currently. Unfortunately, I would say, adjunctive therapy on this layering of ASMs is just a common practice. There is no reason to be worried concerns about the combination. If anything, again, I urge everyone to look into Slide 23. This is the lowest rate of side effects on the therapeutic developments or developed for content seizures despite the fact that the combination was probably the most aggressive at baseline.

So no concern whatsoever. -- we need to deal with the market as the market stands and that's what we are doing here. Particularly with over like 30% of patients on Senorita I would say that's what the market is. We are very confident that both the feds and the efficacy are incredibly strong there. So no real expected change other than the instructions, as we mentioned before, for physicians to be more cautious about the reduction on the background ASM.

Our next question comes from Ritu Baral with TD Cowen.

I just wanted to ask a little more detail on the side effect profile -- and specifically, the comment on the severe patients and this comment about recovered and resolved, can you give us a little more detail on the moderate to the year and serious side effects and that recovered and resolved comment? And then I've got a follow-up.

Yes. Yes. So on the year specifically, 1 of the patients had a dizziness. So I would say that that was clearly like on targets and targets not only for therapy, but for the combinations that they were in. The other ones were background illness, like particularly an infection that leads to aspiration ammonia. So not too concerned about that. The fact that they all like resolved, I think that the most important and resolved very quickly the most important part here. So not too concerned. I think we wanted to be very transparent and show the rates there and show the results, but not anything we're very concerned about.

Was it resolved with removal of drug or adjustment of background meds?

Very good question. Sorry for misunderstanding before. No, it was actually just resolved like with the contingent.

Okay. Okay. That was -- that was the follow-up question. .

I'm showing no further questions at this time. I'd like to turn the call back over to Marcio for closing remarks. .

Thanks, everyone, for joining. We are thrilled on these results. I think it's important for all of us, but it's particularly important for patients living with focused seizures and with epilepsy in general. It's not every day that we've got a field that's been going on for like 100 years since the -- a little bit over 100 years since the first treatment and you can deliver after more than 25 drugs in the market like over -- like 50% production, 60% overall response rate of patients. It's quite remarkable to put in context, I wanted to take a second to show my appreciation for all the patients participating in this study and all the other studies and for everyone at Praxis and our investigators and site staff. Thank you so much. Exciting days ahead of us. I appreciate the support and looking forward to interacting with all of you. .

Thank you for your participation. You may now disconnect. Everyone, have a great day.