To our SMID Cap or to Guggenheim SMID Cap Biotech Conference. My name is Yatin Suneja. I am one of the biotech analysts here. It is my pleasure to welcome our next presenting company, Praxis. From the company, we have Tim Kelly, who is the Chief Financial Officer. Tim, thank you for being here with us. Perhaps you can make some opening comments. Tell us what's going on with the company, a lot of assets that you have, a lot of programs, a lot of trials that are up and running. So why don't you spend maybe five, seven minutes going through some key highlights, and then I'll go into a Q&A discussion, if that's OK.
Yeah, thank you very much. Thanks very much for having us here, and thanks to everybody for joining. It's a very, very exciting time at Praxis these days. And I put that in context of where we are now, maybe relative to where we were this time last year. It's been a very transformative year for us. If I were to go back this time a year ago, we had one asset in phase III with our essential tremor program. We had a couple of other assets hovering around phase II. And as we look at where the company is now, we have four, all four of those assets are in the registrational phase. We are on the cusp of our essential tremor study, starting to get some interim analysis data this quarter that we're excited about. I think we'll probably talk a little bit more about that as well.
Essential tremor is the largest movement disorder. It impacts roughly seven million patients in the U.S., and there has never been a drug designed to help these patients. So we are really at the frontier of drug development for a substantial unmet medical need with the first phase III trial ever in essential tremor. We are using a T-type calcium channel modulator approach in this study. Very excited about how it's progressing, and we can talk a bit more about that as well. The other three assets we have in late stage are in epilepsy. We have two of those programs, our sodium channel modulators. They come out of the same research effort internally. One we are developing in common epilepsies called vormatrigine, and the other one is called relutrigine that we're developing in more developmental rare epilepsies.
We are, again, very, very excited about both of those because the sodium channel is implicated in all seizure activity. There are a number of drugs that have been developed that are a sodium channel blocker, but I very intentionally use the word modulator because these drugs have properties that are acting on the more implicated currents in seizure activity in the sodium channel, the ones you really want to attenuate, without compromising the steady state current that still needs to function in order for the sodium channel to do what it needs to do in our bodies. And so we seem to be hitting the sweet spot with these molecules. They are very potent. They've been tolerable at high levels. We've seen MES fold data that really has never been seen before.
So with vormatrigine, we are currently enrolling two studies: one called RADIANT that is an open- label, 50-patient study that will read out in the first half of this year. And in that one, that's the first time that we're going to be getting efficacy data from this drug. We did a type of study called a PPR study that read out last year. And at the time, about two years ago when we kicked this off, we did not have a lot of money. And so it was a way for us very efficiently to de-risk the program. That study went very well. It gave us a binary signal on activity of the mechanism, but now we want to see how well does the drug work.
This RADIANT study will answer a lot of other questions for us, and it will also inform the dosing for one of our pivotal studies. So that's another catalyst that will read out first half of this year. The second catalyst we have with vormatrigine is our POWER1 study. This is the first of the two registrational studies that we'll do in vormatrigine, and that is up and running right now, and we'll look to read that out in the second half of this year. The other drug we talked about in the sodium channel approach is relutrigine. This is a drug that we're investigating in developmental epilepsies. We read a study out called EMBOLD last September where we looked at 15 patients with very, very severe developmental epilepsies with SCN2A gain- of- function and SCN8A mutations.
We had 15 patients in the study, and what we saw was over the four-month period, a 46% placebo-adjusted reduction in their seizure frequency. We also saw that these children who had an average of about 55 seizures per month going into the study, that a third of them went for at least one month, if not more, without any seizures, which was completely mind-blowing data for us to see. Really, really exciting given how severe this disease has been. We immediately after the readout initiated a second registrational cohort for this EMBOLD study that is currently enrolling and very active. We expect to read that out in the first half of 2026 and to be able to file the NDA for that in 2026 as well.
Because of this sodium channel approach being implicated in all seizures and all developmental epilepsies, we see a lot of applicability for relutrigine also in all developmental epilepsies. So we are in active discussions right now with the agency on aligning on a trial design for relutrigine in all developmental epilepsies that will be called the EMERALD study. And that's another one that we look to get off the ground in the first half of this year. The fourth of our assets that's in epilepsy as well is called elsunersen. This is an ASO. And this is also for SCN2A gain of function patients. We did a small study called EMBRAVE Part 1 of that study back in December of 2023.
We shared some data where these four patients who had been taking it over a four-month period had a 43% reduction in their seizures, a 48% increase in their seizure-free days, which again was data that really was far ahead of what we expected. So we have also taken that to harmonize a protocol there with the U.S. and the European regulators, and we'll be getting a registrational study off the ground very shortly for elsunersen as well. So all four programs are firing right now. It's a very, very exciting time for the company, definitely.
Very good. Thank you for that overview. So let's focus on the essential tremor program. Two studies going on. I think everybody is focused on these interim updates. Could you just help me understand, number one, where are you on the enrollment front? What are certain scenarios that are at play both for Study 1 and Study 2, and when should we expect the interim update and then full data?
Sure. So what we're doing with the trials and what we call the Essential3 program, we have one of the phase III studies is a traditional drug and placebo arm study. We are looking at 200 patients in each arm for a total of 400 patients. They are dosed for a 12-week period, and what we are looking for is a reduction in an endpoint called the Modified Activities of Daily Living that is based off of the validated TETRAS Activities of Daily Living scale with a couple of adjustments based on feedback from the agency, and then the second study we're looking at will enroll up to 200 patients. It's a randomized withdrawal study where patients are dosed for eight weeks on drug, and then based off of a predefined response criteria, patients are either randomized to stay on drug or to go on to placebo.
We've used the randomized withdrawal design a few times before with this drug, and we've seen very, very strong effects using that trial design, so glad to be able to incorporate that in the Essential3 program. The recruiting that we're doing for this, we're doing something quite interesting that both studies are recruiting under the same protocol, and so the enrollment and the interest in this study has been incredibly robust. We have through January highlighted that we've had over 130,000 patients who have come to the study site to express their interest in the study since November of 2023, so roughly 10,000 patients a month. We've all been in healthcare for a while, and I think very rarely do you ever see a study get that type of interest in enrollment.
I think it highlights for us just how substantial the unmet need is for these patients and how much they're looking to have a drug that can help them. It also gives us quite a number of patients that we can be selective for as we're going through enrollment. So enrollment continues to be very robust. We haven't commented on specific numbers there, but we have a very rigorous protocol in ensuring that we can only bring the best and most applicable patients into the study. In terms of Study 1, we built into that study a statistical analysis interim, really with the perspective that we learned a lot out of a phase II-B study we read out in March of 2023 called Essential1. That study missed the primary endpoint, but it hit a lot of the secondaries.
As we were interrogating the data, we learned a lot about a better endpoint that we evolved and we're using now in the Essential3 study. We have increased the sample size significantly. We've done a number of other things from a study conduct perspective, really challenged ourselves on how do we de-risk this phase III program, knowing it was going to be the first one. That all said, we also recognize that it would be a shame to get to the end of the study and have something like a 0.07 p-value.
We have built into the study this interim statistical analysis where at roughly a 50%-60% information fraction, we will do a cut of the data that will go to a predefined group of our statistical board, and they will be looking at do we have sufficient powering in the study, and do they have a recommendation for us to either continue with the study or to add patients as well. There are a few outcomes that can come from this. This statistical analysis will be happening this quarter. That's one of the things that there's, I know, quite a bit of interest in right now. I will confirm that it will be happening in Q1. When this interim review board analyzes the data, they'll come back with a few different options for us, essentially four, I would say.
One of the options, and just to put it on the table, they could come back with that we think is very unlikely, but is futility. Now, they are in their paradigm. There is a lot in the algorithm for them to use a conditional probability perspective where they would recommend adding patients and adding to the sample size, and so futility, we think, is unlikely and actually less and less likely given that they could recommend to us to add more patients so that we achieve statistical significance, so just to put it on the table, that's one of the options. The other three options are about continuing the study in different parts of the study, so we think the most likely outcome is that they will tell us to continue the study as is.
And what that reflects is the assumptions we made about the study that powering it with 400 patients. The study is powered to a 90% confidence with a 0.3 effect size. Operationally, we're seeing it going well. What continue as is reflects is our assumptions were correct. Now, there's a place on either side of that where there could be two other outcomes. One is that they suggest we add more patients based off of they might see the line separating, but adding more patients would ensure the powering and a successful outcome. They will give us a recommendation in bands of 50 patients. So they might say 0-50 or 50-100, and we will take that on and look to adjust the sample population based on that. We're at a rate right now of randomizing about 15-20 patients a week.
And so, every 50 patients they would suggest is about three or so weeks that it might add to the timeline there. Then we'd bring those patients in and read the study out. There is also an opportunity that they define that the study has actually hit the efficacy bar already. There is a very high p-value bar that's required to do that, a 0.003 p-value that needs to be achieved, but that's also on the table as a potential outcome as well. So we're looking at a range of outcomes that can come from this interim analysis. Once we have the results of that, we'll share that with everybody. Also, what the update and the timeline will be for the Study 1 to read out and also the Study 2 with the timeline we think for that will be also. That's the randomized withdrawal study.
Okay. So if you get these, let's say one of these outcomes where the board say, you know, do not increase, do you still have the ability to increase the sample size? Would you do that? Are you sort of follow? You have to follow their guidelines?
So they give us a recommendation, and it's up to us to take on their recommendation, which we would take very seriously, what they suggest. I think the reality is, when we do recruiting and you bring patients into a study, we do have some withdrawals. We have some people that come out. So you never exactly know that you're going to end on exactly the 600. So we always bring in a few more patients. And I think that would also give a touch more powering as well. So we would look to bring in enough to ensure that we're going to hit at least our minimum number there. That may end up having a few more patients at the end, but that's probably how we would take that one on board.
How long will it take you to analyze these data? You might have taken it. You might take it in the future, but just trying to understand how long will you take to analyze it and what will you communicate to the street?
It's a two- to three-week process between when we've decided that we've achieved between that 50% and 60% information fraction. We have to cut the data. We have a team internally who's walled off seeing that. They send the data to the board and their analysts. They take a look at it. They meet. They look at it. They come back to us with what they found. And they give us. It's very simple responses that they'll give us because anything that they would tell us more broadly about what they saw statistically could end up eating into more of the powering assumptions. And we don't want to do that. Based off of what they come back with, we will digest that, take that on, and then look to report that out very soon.
We would be in a place to share what their recommendation was if it was to continue adding patients, what that might mean for the timeline. If we end early, we would also want to do a data clean ourselves and validate that recommendation before we shared it with anybody, and then in the unlikely scenario of futility, we would share that also.
Okay. So in that scenario of futility, would you continue or you just stop the study or you keep on enrolling fully and just complete the study? You'll complete it?
Yeah. I think where we would be, their recommendation would be to stop for futility. We would take that on board and actually operationally, we would run through the rest of the patients who we have. I think we believe that's going to be unlikely, but this is the largest study that's ever been done. There is a lot of information to contribute to the field as well, and we would want to provide that.
Got it. What are you doing to Study 2? Are you touching that study in the sense that any interim you are taking a look at now? What are certain scenarios around that Study 2? If you increase the size, will that get increased as well? Just help me understand that.
Yeah, very good question. Study 2 is not involved at all in this statistical resizing. Because it's a randomized withdrawal, it's an event-driven study. And so we have powered the study to achieve a certain differentiation of events between patients who stay on drug and then those who fail. And so it does not lend itself to being updated for powering. The one thing where both of the studies are linked right now is because of the recruiting protocol. And what would technically happen is when we get the interim analysis back and if they were to suggest either stop early or to add more patients, it would decouple that recruiting and then Study 2 would be a bit more independent in terms of how patients are getting funneled into it.
Okay. For the Study 2, I mean, are you able to track the event rate and how are they tracking right now versus your expectations?
Yeah. So there is a group within the company that's walled off to be looking at that to ensure study conduct, but that's all part of the blinded data that I do not have visibility to.
Okay. Once you have achieved all the events, is it actually not a different question. Let's say both studies continue together. Will you announce data from both studies together or you still could do a separate announcement?
We could do a separate announcement if the events from Study 2 hit their bar first, so there's a chance, and we'll know more about that, I think, when we're on the other side of the interim analysis as well.
Got it. What is your view on the filing package? So if these two studies are successful, what would be the gating factor and where are we on the safety? Because I think safety can be sometimes a sticking factor with the FDA, especially the neuro division.
Yeah. We've been very fortunate in our discussions with them that they have recommended the minimum requirement for the safety bar. So 300 patients in six months, 100 patients for a year. I think it reflects that they believe that it does not require more than that from the safety package, but all of that is well in line so that we, by the end of this year, in 2025, we'll be filing the NDA. And we've also done all the other work that's required for CMC, HAP studies, DDI, all that goes with the filing package.
Yeah. One more question on this study before I go to vormatrigine. How is the study set up in the sense that how many patients you can add at the max, right? And let's say if they come out and say you need to add 150, 200, would you go that far? And what will then imply to the effect size?
Yeah, it's a good question. So the statistical board has a lot of latitude to recommend quite a higher range on the number of patients. I think there's a place to say if it gets to above 200, which is roughly one arm of the study, we'd probably need to do a bit of a think about what is that saying in terms of effect size. But that doesn't mean that we would not go ahead and do that. And I think what's helpful for us is because of this depth of the patients we have in the enrollment funnel, we would be able to execute that as well.
Got it. Going on to vormatrigine, so RADIANT study. So this study is enrolling FOS patient and generalized patient. Could you talk about the type of patient we should expect, the split between FOS and generalized, and what should be the bar? What exactly are you looking for there from an efficacy perspective in both these subsets?
Yeah. Our expectation is that we would file the general population for patients with these diseases. So about 70% focal, about 30% generalized. We open it up to generalized because we don't have a lot of experience with generalized patients with this mechanism, and we see that as a potential for future development. So it will help us understand that better and de-risk a broader program in generalized. What we would expect to see on the focal side is generally, so this is a single-arm study. We don't have placebo, but you generally see about a 20% placebo rate in other focal studies. So we would be looking for a 2x, 3x improvement on top of that. The bar that we see from, I think the Xenon program is a great bar. XCOPRI is the best on the market right now.
They've had about a 30%-35% placebo-adjusted seizure reduction. And so we would want to be in play with that as well. And then also looking at tolerability and how patients are doing, if we also see an improvement in seizure freedom, which is really the holy grail for what we aim to provide for these patients. For generalized, the bar is a little bit lower because there's a lot of therapies that don't work as well there. So we'd expect more to 20%-30% there.
Okay, and the patients that you are enrolling here, how sick they are, how many AEDs they have been on, and are there contraindications, particularly, what about some of the sodium channel if they are on?
Yeah. So we have an inclusion of about two seizures in the previous 28 days. A little bit different than a lot of the existing phase III studies have a requirement of four seizures in the previous 28 days. So some of the feedback we've gotten from KOLs is it opens that up to more of their patients. You might be good candidates for this. And we are allowing for one to three background ASMs as well and no limitation on what that would be.
Got it. What dose are you using in RADIANT and how it is similar or different than POWER1 and POWER2?
So in RADIANT, we're using a single 30 mg dose. It's an oral once-a-day pill. There is no titration. We believe 30 mg is more than sufficient. We've seen about a 15-fold MES with 15 mg or 30 mg. So we think it delivers a lot of potency there. It's been safe and tolerable in the phase I studies that we've done. In the POWER1 studies, so this is the first of the two registrational studies, that trial design there, it's a 12-week study and patients on the drug arm will start at 20 mg, which we also believe will be sufficient for efficacy. And then at six weeks, they will escalate to 30 mg. We designed it that way to learn a bit more about the patients in, we think, a fairly concise way.
One, for patients who respond to 20 mg, we'll learn do they respond better at 30 mg. We will also learn if patients don't respond at 20 mg, do they respond at 30 mg? So in a single trial, we can actually learn a lot about dosing and how patients are responding. The RADIANT study at 30 mg will also inform our second registrational study that we'll call POWER2. This one will get going in the second half of the year. That we expect to be a three-arm study. And we'll learn from the RADIANT study with 30 mg what kind of response we get there. And if we want to carry that through into POWER2, or do we want to go even higher? We have in our phase I MAD study gone as high as 45 mg and seen that to be tolerable as well and continued potency also.
So we've got a bit of variability and we want to be very thoughtful about what we bring into that second registrational study.
Got it. How is the POWER1 up and running? How is the enrollment there and what is the official guidance for data?
So enrollment, we're looking at sites in Europe and the U.S. A lot of enthusiasm for it continues to begin an uptake with enrollment, getting sites going. What we're looking at is a top-line readout in the second half of this year.
Okay, and then the RADIANT comes in the first half.
That's correct.
First half.
So it's a very eventful year for us with vormatrigine.
Indeed, indeed. Maybe in the last minute or so, vormatrigine, what's the update there? Do we expect more EMBOLD data and then the plan for the NDA there in the interim?
Yeah. So the EMBOLD data, we're looking at the second cohort enrolling about 80 patients targeting SCN2A and SCN8A patients. The interest in the study has been robust, so we're really glad to see that. I think this is an exciting therapy for these patients. We're looking at a first half of 2026 readout and then filing the NDA in 2026 as well. When we have an update on the trial design for the EMERALD study, that's the broad all DEE population, we're looking forward to sharing that with everybody as well and look to get that up and going in the first half of this year. Once we have that, I think we'll be in a place of giving more updates on the EMERALD study timeline as well.
Indeed, a lot going on. Final question. I think you've talked about some of the plans on the pain side. Just curious if you can articulate how are you thinking about what type of pain indication you are thinking and which asset?
Yeah. For us, it's very early days on that. But when we look at the, I think the value in the interest that Vertex has gotten on their suzetrigine program, and great credit to them for bringing a new medicine to the market and very badly needed. We have two mechanisms that use the sodium channel. They hit numerous of the sodium channels, which we think is a very interesting way to treat pain. And so we thought it merits us looking into that a bit further and seeing about what a thoughtful approach is for looking at our sodium channel approach and going into pain. We'll talk more about that when we do our R&D day in the second quarter this year and what our plans there would be.
But again, pain is very big, so we want to be very thoughtful about how we do that without compromising all else that's going on in the portfolio.
Very good, Tim. Thank you so much.