Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. It's day two of our conference. Really thrilled to have Praxis Precision Medicines here with us. We have 25 minutes. Marcio, Tim, thank you so much for being here, and it's a pleasure for having you. First of all, I want to congratulate you on an incredible 2025. I remember sitting here last year, right? I think the stock had traded up over 550% or more? Like, it's been really fun.
Positive number.
It's a very positive number. Yeah. And we're very, very proud and excited for you. The team, let's go sort of in chronological order of, again, a very catalyst-rich 2025 that we have ahead of us. So if we go in order, the first thing that we're going to get in Q1 is the essential tremor interim analyses. And we've been getting a lot of questions around that interim. So I guess the first simple question is to remind us what the possibilities are in Q1 in regards to the Essential1 and Essential2.
Yeah, absolutely, and thanks. Thanks. Yeah, it's always an incredible pleasure to be here as well. Maybe I'll use this year as a little bit of a background for the readouts next year, right? So when we started the year, the uncertainty was, like, how well we're going to be able to execute the two studies. It's a very ambitious feat that we put together, like parallel execution of two larger studies. It's actually not done that frequently through parallel, like both studies are recruited at the same time on Essential3 program, Essential1 parallel group, Essential2 stable responder randomized withdrawal. We're in a very good place right now. We're going to discuss that in a second. Then we had incrementally positive data on the program for focal onset seizures and our generalized seizures as well. Then EMBOLD data for our GE portfolio, and here we are, right?
Like getting ready to a very successful 2025 as well. So none of this is by chance, right? Like that's the way it's being planned and arguably executed really, really well by the company. So as we sit thinking about the month ahead, really here, January and beyond in 2025, the first, I would say, major update, of course, always incremental updates and things that happen quite continuously with us, is the interim analysis for Study 1 on the Essential3 program. A lot of the questions, as you just mentioned, is like why and what are the potential scenarios here in general. If you look at face value at Study 1 at the interim, and if you use the lowest possible information fraction, we just closed before, or the Study 1, which is 50%, that study would be bigger than our previous Phase II by about 1.8-fold, right?
About twofold. So of course, if we see exactly the same thing we see in the study in the phase II, we would feel pretty good about the direction of the interim. So that's the first one. The way we intend to disclose this is really whatever the IDMC hands over to us, we're going to be making a communication about it. We think about likelihoods a priori, knowing prior likelihood. The base case is the study continuing to completion. I think there's an upside case there for the study being declared positive at interim. That is the next scenario. That would be an increase in the sample size. And then, of course, there's a low scenario there. That study would be futile. So when you look into the 90%+ probability of the zones are between increasing the sample size and declaring the study positive.
So for those scenarios, maybe it's what's worth talking about, the timeline. Calling the study for overwhelming efficacy is easy, right? The day of the announcement, the study was declared. This is the final analysis for that study, so on and so forth. What is the relationship between that and study two? Study two being the randomized withdrawal. So shortly thereafter, we might need like a month, a month and a half, depending on that point in time to release the data, just wrap it up the entire study two and count the events and things like that. I would have study two as well. Because study two is intrinsically less risky just by its very definition than one. I think everyone should feel really good if that's the case. I think the second scenario here is that finish both studies.
And we would finish those studies, would give a timeline at that point in time. It's unusual to be in a position we are in where at the time of the interim readout, the study would be done, right? So we would really just need some time to complete a few assessments and clean the data and so on at that point in time. Likely like almost complete or really totally complete. We'll give the deadline there as well. And then there is the third scenario where it would increase by a factor that we're going to be given to us by the IDMC. So if you are in that situation, let's pick a number here for the sake of this conversation. 100 patients increase would give you the timeline for that increase, right? On that case, we think would be probably a few weeks to recruit 100 more patients.
When the readout would be. Now in between, we have study two reading out completely. That would be the sequence of events. With one event, we can end up having three. That's the complex a little bit, but the excitement as well about that.
Okay. I guess recently you've been like, you know, very excited around the essential study in terms of more bullish, and I think a lot of clients have been sensing that. What has led, and I think we will talk also to the commitment of thinking about Parkinson's and getting ready for Parkinson's. What aspect, like what have you seen that has changed your perspective or excitement? You're always a wonderful, the most positive human being I've ever met, but I could even sense a higher degree of excitement as you feel around the essential studies, and what's opaque to many of us is what led to that change.
I've been excited since the 1970s.
Yeah.
The results. Says my mom. But I got a lot more excited. I think as time goes by, we can learn that studies are going similar to what we planned. And because we planned for success, right? Only psychopaths plan for failure. We planned for success this study. If the hypothesis and the assumptions and the data that's coming in is very aligned with that, I think we have to be more excited. As patients complete their study, we have a lot more ability to interact and to understand the experience as well. And I think that increased our level of excitement now. I think we all in this room, either here or virtually, have been wrong 100 times since the sunrise this morning in terms of our predictions. But we got to trust the data that's coming our way and what we are looking forward to this.
So yes, you might have a sense of increased excitement on all of us. But it's maturity of the data, no deviation, quality of the study execution, and really what we are seeing from the patients in general. I think it got us to move from the base case scenario to maybe envisioning like an upside case. That's what we are sensing there.
So for many investors who are sitting on the sidelines and asking a lot of essential interim readouts, they're just trying to understand which scenario one keep as is and read out versus upsizing which of these two scenarios is more of a de-risking event from a POS perspective. So if you are not a shareholder in Praxis and you were looking as an outsider, which of these two things should reflect a higher conviction on success and trigger buying ahead of that data?
Well, I think right now there's not a lot of people sitting on the sideline anymore. And that is a good thing as well, right? The more people looking to the data, the more they I think we got aligned in terms of expectation. So that's one data point. Like when you look into the three top scenarios here, right, increasing the sample size for efficacy is very straightforward for people to understand because it means you are in the zone, you add a little bit more patients, you're going to like the probability of success increase so much when you do that. I think it's intellectually very simple to understand. Despite the fact that just technically continuing the study that was declared to be at the original power is kind of the best other than declaring for efficacy. Of course, declaring for efficacy is ambiguous. It's very clear.
So I'm not sure there's much of a distinction there. For as long as those are the three options that we're in, I think we all should feel incredibly good. Just as a reminder, we tend to forget this. There's over two million patients in the U.S. seeking treatment for essential tremor. No drug that is addressing their needs. So when you put that on the context, like it becomes pretty clear the case here for the drug.
Okay. And then, team, when we think about the, I mean, it's very clear essential ET presents a significant market opportunity and there's been virtually no innovation. Could you help us understand like what do you need to see in the, is any statistical separation in both of these studies sufficient to warrant commercial readiness? Or is there a certain clinically meaningful difference in the modified ADL that we should be thinking about?
So, got to take a step back as well and ask what is the ADL scale measuring, right? And it's not abstract. It's not like a change in a marker somewhere like neurofilaments or something else that only God knows what really means, right? These are changes in what people do. Like you and I, our parents, like everyone else, like being able to independently get dressed in the morning, brush their teeth, drinking coffee, like arguing a case in court, as we heard from some trial lawyers. It's very clear. Like when you gain a function, when you move one point, there's a very clear impact on people's lives. So the statistical planning was done around this idea that one point would be meaningful. But that's only part of the story. Every single drug has a distribution of effects.
We got to ask the question as well, what is the distribution of effects? Like, what is the proportion of patients gaining two, three, four, five, 10 points? And that's the combined analysis of all of this, is going to be quite important for a new drug application in the U.S., a market authorization application in Europe, and so on and so forth. When we do the formal analysis for meaningfulness using the April last year guidance, it's very clear one point would be very clearly meaningful. Obviously we'd like to see the distribution to be quite supportive of a broad effect for this population as well.
Okay. And what work is being done between now and the essential tremor readouts in terms of preparation for phase III or phase II for Parkinson's? If you could talk about what's the key objective here?
Yeah. So we did a fair bit of work on PD before, right? When you look into the overall network, the anatomical region is a little bit different on the thalamus here, but like fairly rich on those channels in general. If you look into the basic reason why DBS, for example, you would work on both, it's quite linked to the T-type calcium channel in general. So we feel very good about the physiology, therefore the pathology and the overall play that the T-type calcium channels have on both conditions. Now, the manifestation is different, right? They're completely different manifestations. So what we had discussions with the agency before is first what they would like to see, which kind of endpoints, what kind of duration. So we have a very good idea there. I think it's no secret to anyone. The UPDRS, certain models, certain duration is clear.
But off periods, for example, are quite important for this patient. So that's something we'll be looking into. We are refining right now the plans, knowing everything we know. We thought it would be important to give a heads up to everyone. We are in the final stages of looking to that. And upon a positive interim or a positive readout, we would reinitiate that program quite quickly.
Investors have recently asked us consistently, saying Praxis knew that there's an opportunity in Parkinson's. And now they want to focus on it and it makes commercial sense upon success. But they just wonder why, what triggered it to bring it back now?
Yeah. It's a system, right? There is no just one factor. I think part of the system is as our confidence in essential tremor increases, our confidence in the overall biology increases, then we have to ask what's next. So that's number one. I think the other is as we expand outside of the door on both the treating physicians and potential strategics that we might or might not want to collaborate with or transact with, there is a pretty high interest because essential tremor is significantly more prevalent than Parkinson's, about seven times more. But there was a lot more work done in Parkinson's. Historically, it's more top of mind for certain neurologists, movement disorder specialists. It's an easy way to leverage commercial success. And it's well understood by other entities in this space as well.
So when you put that all together, the biological de-risking we're seeing and the strategic plus healthcare professional interest became a no-brainer.
Okay. Would love to transition now to 628 and talk about the Radiant study, which is the next catalyst after the interim. It's an open label study in focal and generalized epilepsy in about 50 patients, and it's going to read out in one year, and I think you have said the distribution of 70 focal versus 30 generalized. I guess how is enrollment progressing in the study? The confidence on at what point you can narrow guidance and what would be sort of a population, like a cohort size that would be sufficient to wanting to share data on what the straight.
So we can obviously monitor this study in a very different way, right? Because it's open label. We'll make a determination if there is a point in the future, like or soon in the future, that might be enough data that maturing there that grant us to talk a little bit more about that. But the goal is to read out the 50 patients or so by, let's call Q2, right? So we said first half, but let's call Q2 for the sake of the arguments here right now. And what we're expecting to see there is the promise of vormatrigine or 628 as we develop. Like what we've seen so far, this is the most potent by a mile the drug ever developed in epilepsy. It is incredibly convenient. It seems to be fairly safe.
The thing here is because the data sets are still small, but we're not seeing anything. We reach certain PK to PD tech levels that have never been reached before. Put that all together. Now we bring that drug to patients, we should see very clear results on the control of their seizures, which would allow us to, one, maybe have certain regulatory discussions I would like to have on a profile like that, accelerate the development of other things, and really enable Power2. That is the second study, controlled study. There's a lot in that study that's going to be helpful on top of learning a lot about the pharmacology in patients. We have a lot of pharmacology in healthy volunteers, but we think we could use a little bit more in patients. That is re-enrolled in parallel to Power1.
So intentionally, we separated the sites and the geography. I feel very confident about enrollments, but it is a little bit more restrictive, the number of sites for Radiant because we had significantly more interest than we would be able to open sites. And we didn't want to upset many people. So it's an exclusive European and Asia-Pacific, so Australia and Europe study. There wouldn't be an opportunity to add more countries at this point in time because of the overall interest, which contrasts to like Power1, which is our double-blinded placebo-controlled 12-week study, one-to-one in focal epilepsy alone, where there are more geographies involved. I would say more traditional, the U.S. is a big part of that.
When you put those together for next year, since both of them are expected to read out next year, they create a quite nice overall background for the focal epilepsy and generalized signal for this study. You talked about the 70-30 focal generalized for Radiant. And that's what we expect. It might be 5% here and there, not exact, but that's what we expect to have.
You have, in a previous fireside chat, spoken about the bar for success in Radiant to be about a greater than 20% increase seizure reduction. Where do you get that 20% from? And then question two is, do you think the 20% will be sort of similar between the two populations, or is there going to be a divergent treatment effect?
So maybe one small correction there or change, right? When you look into historical placebo rates in focal, that is this urban legend on how they kept escalating and so on. And I love that because when you actually ask for the data, the data does not support that at all. That is anywhere between like high single digits to mid-teens is where virtually every study lands. So when you look into that, and because there are several studies, we don't need to be like biased by one or two, right? I believe like a multiple of that would be unequivocal that it's the drug versus potential like variability in placebo. So when you look into like, call 15%-20% as the variability that we might be able to see at double of that, 1.5 times double, that's where we would like to see the drug behave.
There is no real base rate for the generalized. So I think on generalized, the sky is the limit for us here. I would like if I had this one of my many desires in life would be for these patients never to seize again. Those are incredibly disruptive and life-threatening for them. So if we can get a good proportion of patients not having any seizures as we've seen on our GE study, that would be fantastic as well, and we're looking forward to seeing that first half of next year.
Maybe for Power1 and Power2, remind us, what are the powering assumptions? What would be a competitive product profile as those will be reading out in the second half of 2025?
That's right. So Power1 reading out at the time frame, right? It's a little bit over 200 patients, one-to-one, randomized more than seizures, four seizures at baseline or previous four weeks. What we expect to see in these studies and how they get formally powered is significantly less than what we actually expect to see. I look into all the power calculations, they all assume about 15%-20% difference. Of course, we expect to see more than that. So it's incredibly well powered for an effect size that we believe is going to be smaller than what expects from this drug. The drug to beat here is phenobarbital. Patients do really well from a seizure control on that drug. There are many other issues why it's not the most used drug in epilepsy today. No fault of their own, it's just like how it ended up being.
But if you can deliver the kind of seizure freedom, the kind of seizure control reduction on that drug with no titration, most potent drug, most selective drug ever developed, driving that to patients very little to no DDI, no food effects, you name it, right? That 628 can bring and no one else can, right? That's the only profile that vormatrigine or 628 can bring. There is no comparative profile in development right now or in the market, then I would say why use any other drug?
Okay. And maybe I know we have like 45 seconds left. So on PRAX-562, I mean, you initiated the cohort two, which is ongoing. Maybe thinking about how do you expect in cohort two, there's definitely a lot more patients. How quickly can you enroll that group, have data? And at what point can you also come back to us and discuss the regulatory framework for pivotal studies?
Yeah. So cohort two for SCN2A and SCN8A is the registration cohorts for EMBOLD, right? So that we are set, that should serve as the registration cohort. We started about two months ago. It's going incredibly well. And I say that with a little bit of reserved optimism. We did not guide yet for the completion of that, but I think we all feel incredibly good that we're going to be beating our own internal timelines on that study. And on the second study on Radiant for the larger GE population, we do have a meeting set with the FDA. We're going to be discussing the registration of pathway there. We're very positive about finding a common ground to develop the drug, which we believe could benefit over 80% of the patients with GE in the market. So that would be about 150,000-180,000 patients in the United States.
What is your expectation in terms of placebo? I think when you reported the September data, did a great job on execution and came up with a low placebo and people were shocked by it, right? Just maybe last question on what are your expectations there as in cohort two?
It's funny when you do something too well and people are shocked by it. But so, congratulations to the team, definitely not only on that and all the team at Praxis. The placebo in pediatric studies for epilepsy is always very small. It might not have been as small as the one we showed because we probably did a better job there. But even if you look into like across the board, it's probably over around 10% or so when it's properly done. I'm not going to talk about people who don't know what they're doing here and anchor on that. So I actually don't think it was quite as exceptional. It's like 1.6% is definitely very good.
But even if we have something like that, even if it's a little bit more, when we're talking about drug being four and a half times bigger than that placebo effect, you just don't have drugs like this in development. So we're insanely bullish about relutrigine and ulixacaltamide.
Yes. We will be using that in our note and quotation. Thank you so much. Congrats on a very successful 2024. And we're very excited in 2025. Let's applaud Marcio for a great discussion.
Thank you. Thank you.