All right. Hi, everyone. Thank you for joining today. My name is Franç Brisebois. I'm one of the Biotech Analysts at Oppenheimer. Our next company presenting here is Praxis Precision Medicines. From the company, we have CFO Tim Kelly to join. What we'll do in terms of format here, we'll just do a fireside chat. Thank you, Tim, for joining. And yeah, if you have any questions at all for the listeners, you can email me or send it in the Q&A tab. But yeah, Tim, thanks for joining. It's obviously a super busy time for you guys right now, so I appreciate you taking the time. And on that note, maybe just a quick intro on yourself and the company background for those that don't know, but this has been a pretty hot one here.
Great. Thanks very much, Franç. We really appreciate being here today and Oppenheimer's invitation. It means a lot to us, so definitely a very exciting time for us at Praxis, and we began 2025 really on the heels. It was a very transformative 2024 for the company. We were founded back in 2015 based off of the neuronal patterns that are expressed in epilepsy, where we see a lot of over- or under-excitation in CNS pathways and recognizing that that's a way to identify mechanisms for a breadth of CNS diseases, and as the portfolios progressed, we now are at a place where we have four assets in the clinic. What was transformative for us in 2024 is we really got our first phase III study off the ground at the end of 2023, going into 2024 in essential tremor. We'll talk about that in a few minutes as well.
But we also shared some data in our common epilepsy program called Vormatrigine , which is a sodium channel modulator. Also some very exciting data in Q3 last year in our DE-focused sodium channel modulator called Relutrigine that we've now moved into a registrational study as well. And then finally, we've aligned on a registrational study for Elsunersen ASO and SCN2A gain-of-function patients. So a lot of activity and progression on the portfolio in 2024 that sets us up into 2025 that we've now got four assets in late stage. We will this quarter be doing an interim statistical analysis on one of the studies in our essential tremor program. I know we'll spend some time on that. We have a couple of catalysts also in our Vormatrigine common epilepsy program with our RADIANT study and our POWER1 study.
And then I think later in this half of the year, we'll be getting off the ground our two developmental epilepsy studies in Elsunersen and Relutrigine as well. So really exciting time for us and a lot we can talk about.
Yeah, it's difficult to fit it into this discussion here, but I think we have to just because the interim analysis, the interim statistical analysis update is supposed to be happening this quarter here. So just have to talk about essential tremor. It's obviously been a difficult space. Can you just, for those that aren't familiar with it, just remind them a little bit of ET and how big the space is?
Yeah, absolutely. So essential tremor is the largest, most common movement disorder in the U.S. It's estimated about seven to eight million patients in the U.S. have essential tremor. We believe the addressable market is probably two million of those patients. Those being patients who are moderate to severe, who are either on treatment and not adequately being served by their pharmacopeia or who are seeking treatment. That two million compares to about a million patients with Parkinson's disease. So you get a sense of just how much larger essential tremor is. There's never been a drug designed for essential tremor. So we are really on the frontier of new innovation for these patients with the first phase III in essential tremor. I think we'll probably address as well. There have been some failures in the past.
I think if some of them due to maybe a mechanism that didn't work as well. There was another competitor that failed in this space last year. A couple of different reasons why that might have happened between drug potency or trial design. I think a lot of those issues that we've addressed as we've learned through our phase II program and applied those learnings into the phase III design that we currently have. I think one of the most interesting things that we've seen. We started enrolling the study in November of 2023. Since then, we've had over 130,000 people who have expressed interest in participating in the phase III program, which is just an enormous amount of people, almost 10,000 a month.
I think it speaks really to just how huge the unmet medical need is for this, how much patients are looking for something for their disease. It's also supported us to ensure that we're getting really the best and most qualified patients to come into the study as well.
Okay. Now there's a lot there. So, what I guess that you discussed a bit: the failures of others in the past. What about your design has maybe been? What are the learnings, and why are you guys different here?
Yeah. So we did. I referenced we'd done a previous phase II study that was called Essential1. We shared the results from this in March of 2023. And we used a composite endpoint for that study. And we missed the primary endpoint. And so we're very open about that. But we hit a lot of the secondaries. And we had a tolerable safety profile. And we really interrogated the data. And what we identified is out of the composite that we were using, there was one side of it called the performance scale, where there's actually very poor concordance with how this study is undertaken and measured. It's a decent scale to use if you're assessing if patients have disease, but in a clinical trial setting where we're trying to reduce variability, it's just not appropriate.
So we took our findings and our recommendation to the agency as part of our end of phase II meeting and recommended an endpoint that's based off of the TETRAS Activities of Daily Living Scale. That's a 12-point scale that's assessed from a zero to four severity by the physician through a structured interview with the patient. The agency made two suggestions to us, one that we collapse the scale to be rated from zero to three, and then secondly, that we remove an item about social impact from the primary endpoint. So we're including that in our secondary endpoint, but not in the primary. But what this Activities of Daily Living Scale captures is for a patient to share how is the disease impacting your life on items like drinking or getting dressed or how you're able to use keys.
It's a variety of aspects that what we would look to see is a reduction in the score over the 12 weeks that patients are on the study as a reflection of how the drug is able to reduce the disease's impact on their daily life. So what we've seen out of our previous phase II study is we had about 120 patients in that study. We also had a subset of patients who have a type of essential tremor called intention tremor. And they actually have more variability in their disease, the way it manifests itself. And it's something that we didn't control for previously. So if we fast forward to the phase III design that we currently have, we're using an endpoint now with the Activities of Daily Living Scale that we think is much more appropriate.
We have 400 patients in our placebo-controlled arms, study one. So almost three times the statistical size or sample size there, so a lot more powering. We're also stratifying for patients with this intention tremor. That's one of the three factors we're stratifying for. Also for familial history, as well as patients who are on propranolol, which is the only drug that's approved for patients with essential tremor. In addition, we also, in the conduct of the study, evaluate patients for consistency in their baseline before they're randomized. And so we believe that this is a way to check that we're getting patients into the study who are consistent on this Activities of Daily Living. We check for them a couple of times before they're actually randomized.
And patients who are too variable, we do not allow into the study, but we believe that's bringing patients in who will reduce some of the placebo effect as well. So a number of things that we've done from a powering perspective, from a controls perspective and execution side, in addition to the statistical interim analysis that we'll do shortly as well that we think is an additional insurance policy.
So on that, I think it's very important for listeners to understand that that interim analysis is only on study one, not on study two of the Essential3, correct?
That's correct, so a little bit about what we've designed, and our Essential3 program is actually two studies. Study one is a two-arm placebo-controlled study, 200 patients in placebo, 200 patients in a drug arm on 60 mg for a 12-week period. That's the one where we're doing the statistical interim on. The second study is a randomized withdrawal study with up to 200 patients, and we've actually done randomized withdrawals with this drug a couple of times before. We had a phase II way that we shared data from in May of 2022. We also did an extension study on this Essential1 study I talked about as well, where we tested the randomized design. What we see is for patients who respond on ulixacaltamide, when you remove the drug, they rebound very quickly.
And so they go through that and then they attenuate back to their baseline. So it's actually been a very, very effective study design for this mechanism. So the second study we have is this randomized withdrawal where patients are given drug at 60 mg for eight weeks. And then at an eight-week period, we have a pre-specified response criteria. And patients who have triggered that response criteria are then either randomized to stay on drug or to go on to placebo. And so we measure a difference between those who maintain effect versus those who lose effect. And that's what the endpoint is for that second study.
Are there parts of these trials that are actually identical? Do the patients know what study they're in? And do the doctors know what study their patients are in?
Yeah, no, great question. So the way we've designed the study is it's actually a single recruiting protocol. So we are, through one effort of, I mentioned these 130,000 patients, they go through a single recruiting funnel protocol screening, all of that. And it's only when they get to the bottom of the funnel that they are then randomized into one of the two studies. And they are not aware of which study they are on. The nurses, this is done entirely decentralized in the patient's home. And the nurses who go to the home don't know which study they're on. The physician investigators who are meeting with the patients don't know which study they're on. So we believe that also is supporting a lot of the powering that it's randomized between which of the two studies patients are participating in.
Okay. And I don't have a choice. I know you've talked about this. You've probably answered this question a thousand times here. But the way the investment world works, there's a lot of different outcomes here. It's not just a good or bad sort of thing. So off this interim update that's coming up here, what are the possible outcomes that can come out of this?
Yeah, so there's a few different outcomes. What we believe is the most likely outcome is that our assumptions on powering, on how the data is reading out, we're going to do a clip of the data at a 50%-60% information fraction and share that data with this statistical review board. They will look at it and come back to us with one of these options. The most likely we believe is our assumptions are correct and they will say carry on and continue the study, and that would reflect that it is on track to achieve a statistically meaningful outcome in line with the information powering that we've set up for the study. There is also a chance that we were conservative on our assumptions and that the study ends for efficacy. In order to do that, we need to achieve about a 0.003 P-value.
So there's a very high statistical bar in order to end for efficacy, but it's on the table as one of the outcomes. An equally likely outcome is that we were a little conservative, aggressive on our assumptions with the powering, and we actually need to add some patients, and so the algorithm that the statistical review board will evaluate is what are a number of patients that could be added to the sampling to ensure a statistically powered result coming out of it at the end in tranches of 50, so they might say add zero to 50 or 50 to 100, 100 to 150. What that would reflect is the lines are separating, but need to add a few more patients to ensure that we hit statistical significance at the end of the study, so three different ranges of what are overall positive outcomes for the study.
The last outcome that we think is very unlikely because of this conditional powering methodology that the board is using is for futility. So we think that's a minority, very small chance of happening, but for the sake of completeness, want to ensure that people understand that is a potential outcome as well. When we get the results from the interim review board, they will not tell us very much. They are essentially going to say, here is the option that we selected and the recommendation that they make. And our expectation and commitment is that we will share that update with the investment community. And from there, we'll be in a much better place to also give an update on the timing for the full readout of study one and also study two.
So this is all on track to happen in Q1, and we're looking forward to getting to that point soon.
The key word there, these are recommendations.
Correct.
And there's.
So they will give go ahead.
I was just wondering if there's any upside other than the data reading out quicker and all that, but is there any upside, like why not increase the end number, I guess is the question.
Yeah, I know it's a good question, and I think realistically, it's very hard to end on the exact number of patients because you do have some dropouts as you go through, so we always over-enroll a bit, and sometimes you can do that up to 5% or 10% more patients just to ensure you get enough coming out at the very end of the study, so given the huge interest we've had in this study, we are able to screen a sufficient number of patients, so we can top off and have a few more maybe at the end of this study as well, but I think to your point, when we get the recommendation from the statistical review board, that will be a discussion we'll have internally about how we action all of that.
Okay. And is there a point? Is there a certain increments of 50? There's a lot of enrollment. If it's like over 150 or 200 more patients, is there a point to a stage where it's like, look, we just, we're not continuing. That's too many patients. It doesn't make sense based on the efficacy here?
Yeah, that's a great question. The statistical review board can recommend multiple hundreds of patients, I think up to 300-ish or so. So this is why it's so hard to expect futility to come out of it because they can make a recommendation so much higher. I think realistically, when it gets to about 200, we'd have to have a discussion internally about what does that mean in terms of effect size and the sampling in there. But that's a discussion we'll have if that's the recommendation that comes back.
Study two, though, that's event-driven, correct?
That's correct.
Okay. Can you explain to people maybe what that means?
Yeah, so what we're looking at there is a significantly different outcome in events between patients who, once they're randomized at eight weeks, they either maintain benefit if they're on drug or they fail the study because they go on placebo and they come out. Or they have a, they revert to the baseline. What they need to do is have two consecutive periods after the randomization at week eight when they revert by a certain threshold back to their baseline. And that's what we would consider to be a study failure. And what we're looking for is a statistically proportional difference between those two outcomes. It does not need to be an enormous number in order to show that there is a statistically different outcome there. So we say up to 200 patients to enroll into that study.
We're not at a place yet where we can look and see how that difference in outcomes is happening. But once we get on the other side of this interim, we may be in a place, particularly if we're adding more patients or stopping early, when we could see have we triggered some of that as well. And so that's part of, we just don't know yet what the timeline for that will be, but we want to give some of that update also as part of the interim announcement.
Okay. All right. Perfect. And we can go for a while here, but there's only 10 minutes left. So if it's okay, this one has gained a lot of, has become a lot more important. There's a lot more attention around Relutrigine for the rare epilepsy. So I'd love to jump into that program. Maybe if you can tell us a little bit about the data you have so far, why it's encouraging, and updates going forward.
Yeah. Relutrigine, I think, is a really great program and a really exciting molecule. And I think it will be one that we'll spend a lot more time on as we get into this year as well. So as I referenced earlier, this is a sodium channel modulator. And the way both Relutrigine and Vormatrigine are chemically formulated, they use the sodium channel approach. But I use the word modulator very intentionally. It's more of a precision-type approach, different than a lot of the existing sodium channel therapies or blockers. And it is a fairly blunt instrument that tries to stop the overactivity of the sodium channel, but at the same time, it stops the good part of the sodium channel working as well. And we need that as part of our biology and to perform movement.
What Relutrigine and Vormatrigine seem to have hit very well is a new type of receptor that's exposed when the sodium channel is in an overactive state that binds and attenuates the overactivity of the sodium channel without compromising the functionality of the sodium channel. The outcome of this is we are finding we can actually dose to much higher potencies than has previously been done with any sodium channel blocker, multiple folds of what's already either in development right now or even on the market. So we're really excited what that means in terms of how high we can dose and potentially trigger better outcomes for patients because you can do more to mitigate the sodium channel without triggering toxicity tolerability.
So when we had initiated what's called the EMBOLD study with Relutrigine a few years ago, we were at a place where we did not have the cash resources we have now. And we were looking at what is a small, thoughtful study that we could do that would set a very high bar for ourselves that if we were successful here, we would know we could carry the study forward. And so we focused on a very severe subpopulation of developmental epilepsy patients who have a mutation in the SCN2A or SCN8A gene and focused on those developmental epilepsies. Our EMBOLD study that read out in September of last year showed that in 15 patients who were dosed for a four-month period, that they had a 46% reduction of placebo-adjusted in their seizure rates over this four-month period.
Out of those patients, 13 of the 15 carried on into an open label extension for up to nine months. We saw a 77% reduction in their baseline seizures. And to go back, the baseline seizures for this population was roughly 55 seizures a month at baseline. So you can imagine this is an extremely severe population. I think what was the most exciting data point coming out of this is five of these 15 children had seizure freedom for at least one period. And most of them had it for multiple periods as well. And so if you can imagine what that does for their entire caregiver community to go from a baseline of 55, many of them or more, a few less to zero, really, really exciting for us.
As we started seeing some of the blinded data go through, we saw there's a lot of potential for this program. And we immediately opened a second cohort upon releasing the top line data. This second cohort is enrolling 80 patients focused on SCN2A and SCN8A population and a lot of enthusiasm as we're enrolling and recruiting for that right now. We're looking to share the top line results of that at the beginning of 2026. And that would be a registrational study and then be in a place where we could file that NDA in 2026. So that's for a small population of developmental epilepsy patients. But what's common across all developmental epilepsy patients and across all patients with severe seizures is the sodium channel activity.
That really is for as many branches as genotyped patients as we have these days and great science where we keep identifying more and more mutations that are implicated in disease. A common trunk in how the disease is manifest is seizures where there's sodium channel activity. We believe that Relutrigine is a much more optimized molecule to treat the sodium channel overactivity for any type of developmental epilepsy. What we're looking at now, and we're still in discussions with the regulatory agencies, is a trial design that really looks at the entire population of developmental epilepsy patients. From there, be in a place with a fairly traditional trial design looking at drug arm and a placebo arm, showing that across more of a phenotypically driven approach that we can reduce the seizure burden and from there the impact of disease for these children and these patients.
So we're looking to get all the regulatory discussions aligned in the first half of this year and get that up and running shortly and really looking forward to talking about it a lot more.
Do you have, is there an R&D day coming up soon?
Can you say that again?
Is there an R&D day coming up soon?
There will be an R&D day. So we haven't had one since fourth quarter of 2023. So we'll share shortly the date, but looking at the second quarter, it's been quite a while since we've had a chance to go and talk with everybody. And usually these investment interactions are minimized to 30 minutes or 45 minutes. So it's not a lot of time to really dig deep into what are we seeing in the programs, what do we see on some of the commercial potential for these. I think when we look at both relutrigine, Vormatrigine, essential tremor, this is an entirely new treatment regimen to bring to these medicines. So there's a lot to share about how we see a label transforming into innovation for patients and a lot of very exciting market potential as well.
We've also talked briefly that we are going to look a bit into pain as well. This is a place where great credit to Vertex for their new program using a sodium channel approach, and we have a few sodium channel molecules. We had previously investigated Relutrigine and pain, and so it's something that we want to be very thoughtful and kind of evaluating, is there a path where there could be a pain opportunity as well with our sodium channel portfolio, so we'll talk a little bit about some of that as well, and so be on the lookout for a date shortly.
Well, to that point, you make a point of it, but we have two minutes left. And there's focal onset seizures and generalized epilepsy. Any comment on maybe the expectations around the readouts for RADIANT and POWER1 this year?
Yeah. So RADIANT is our open label study for Vormatrigine that we're currently enrolling up to 50 patients, single dose arm at 30 mg. We're looking to read that out in the first half of this year. We'll be recruiting patients both in focal and generalized epilepsies. Proportionally in the population, it's about 70% focal, 30% generalized. We're looking at primarily seizure reduction over an eight-week period compared to a four-week baseline period. This is our first chance also to look at the mechanism in generalized epilepsy. It's a bit more challenging sometimes looking at sodium channel therapies in generalized epilepsy, but Vormatrigine works a little bit differently. This is a way for us to evaluate, do we see some efficacy signals there and de-risk doing a further study down the road. Then you referenced POWER1, that's the first of our two registrational studies.
That is also enrolling right now. We're looking at a two-arm study, dosing patients over a 12-week period, placebo arm, and then we have a drug arm that starts patients at 20 mg for six weeks and then escalates them to 30 mg for the second six weeks. We expect to see efficacy at 20 mg, but for patients who show efficacy at 20, we'll get a chance to see does it improve at 30. If they don't show efficacy at 20, we can see if they respond at 30. So we can learn a lot from this trial design. And then our intention is to start our second registrational study called POWER2 , probably in the second half of the year after we get the RADIANT data because that study will be very informative for us on what the arms will look like for the POWER2 study.
We expect between RADIANT and POWER1 to be two other top-line data results that we'll have in 2025 as well.
Great. And as the CFO, I have to finish with this one. And there was a press release around JPM, just kind of a mention of the balance sheet situation. And you also said that not too long ago, you guys did not have the resources, but it seems like you ended the year pretty strong here.
We did. We ended 2024 with about $470 million of cash. We did have two follow-on offerings that we did in Q1 of 2024. Appreciate everybody's support for that, and with that, I think we've really been thoughtful about putting that money into trials that expand the portfolio while we continue to run a very lean and focused cost structure, so with this cash balance we have, we can fund all of the programs that we talk about today through their top line readout, and our current cash runway gets us into 2028.
That's great. Well, I think we're right on time. Tim, thank you very much. I know how busy you guys are right now, so I really appreciate the time.
Yeah, thank you too.