Praxis Precision Medicines Inc

NASDAQ:PRAX

Earnings Call Analysis

Praxis Advances Key CNS Therapies with Strong Financial Backing

Praxis Precision Medicines made notable progress in Q2 2024, advancing four programs into late-stage development. The lead drug, ulixacaltamide, aims for essential tremor improvements, with pivotal trials expecting results soon. PRAX-628 for epilepsy is in late-stage trials with expected results in 2025. Relutrigine, targeting severe epilepsy in children, will have readouts this quarter. Financially, Praxis ended Q2 with $433.8 million, bolstered by public offerings, securing a runway into 2027.

Setting the Stage for Growth

Praxis Precision Medicines is experiencing significant momentum in its clinical development pipeline, positioning the company to have up to four programs in registrational phases by 2025. This positions Praxis at an exciting juncture in the evolving field of precision medicine for central nervous system disorders. Their lead program, ulixacaltamide, targets essential tremor, and recent developments suggest strong potential as they move toward critical trial phases.

Promising Clinical Data

Praxis is on track to report top-line results from its pivotal Essential3 trials for ulixacaltamide later this year. Concurrently, the relutrigine program is also gaining traction, with top-line results from EMBOLD expected soon, specifically in pediatric patients suffering from developmental and epileptic encephalopathies. The anticipation of these results is high, as both programs aim to address substantial unmet medical needs within their respective patient populations.

Financial Stability Fuels Expansion

Tim Kelly, the CFO, noted that Praxis ended the second quarter with approximately $433.8 million in cash and marketable securities, a substantial increase from $81 million in December 2023. This enhanced financial position provides a runway through 2027, assuring stakeholders that key studies can continue unhindered and bolstered by recent follow-on public offerings. The steady financial health allows Praxis the capability to invest robustly into their innovation pipeline.

Strategic Planning with Regulatory Authorities

The company has engaged actively with regulators, including plans for an interim analysis of the Essential3 program set for Q4 2024. This proactive step illustrates Praxis's commitment to transparency and optimizing trial design based on evolving data. The interim analysis could potentially expand sample sizes to enhance the statistical power of findings, ensuring the best possible outcomes for both patients and investors alike.

Future Growth and Revenue Guidance

With programs like PRAX-628 (focal and generalized epilepsy) and relutrigine aimed at some of the most severe forms of epilepsy, there is a glimmer of hope for revenue growth stemming from new product introductions. Guidance suggests that results from pivotal studies could start generating significant revenues post-2025, potentially capturing a share of the large and under-served epilepsy treatment market.

Emphasis on Patient-Centric Development

Praxis's commitment goes beyond merely financial metrics, emphasizing the importance of patient outcomes. The company recognizes that as they aim for a 20%-30% reduction in seizure frequency through their ongoing drug trials, the overall success will rest on their ability to translate clinical efficacy into tangible benefits for patients suffering from severe conditions that currently lack effective treatments.

Anticipating Upcoming Results

Key milestones loom in the near future, including the anticipated results from the EMBOLD study within the next quarter. Investors and stakeholders are keenly waiting to determine how these findings will shape the trajectory of both ulixacaltamide and relutrigine, with the potential of impacting regulatory decisions and market entries.

Conclusion: A Bright Horizon

The narrative unfolding at Praxis Precision Medicines signals a promising future, backed by solid financial health, innovative clinical programs, and an unwavering focus on patient needs. As the company approaches critical data readouts and expands its pipeline, it stands well-positioned within the biotechnology landscape, offering investors a compelling story of growth and the potential to disrupt treatment paradigms in epilepsy and essential tremor.

Earnings Call Transcript 2024-Q2

[Operator]

Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Second Quarter 2024 Corporate Update Conference Call. [Operator Instructions] Please note that today's conference is being recorded.

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

[Daniel Ferry]

Good morning, and welcome to Praxis Precision Medicines second quarter 2024 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. This call is also being recorded.

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.

Leading the call today will be Marcio De'Souza, President and Chief Executive Officer of Praxis. Tim Kelly, Chief Financial Officer, will also be joining Marcio. After providing updates on our key programs, there will be a brief question-and-answer session.

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

[Marcio Souza, executive]

Thank you. Good morning, and welcome to the Praxis second quarter 2024 conference call. Praxis is driven by our mission to [indiscernible] more as we discuss throughout the call today. We have organized today's call to provide you with a comprehensive update on recent progress on upcoming milestones for our key clinical programs.

I'm very proud of the significant progress we have made so far this year, which set Praxis in a position to have up to 4 programs in a registrational phase by 2025.

We continue to successfully drive our lead clinical program, ulixacaltamide, towards registration, including the execution of our pivotal Essential3 trials in essential tremor, which expected top line results later this year.

Additionally, following the positive PPR results in PRAX-628, we have designed a comprehensive clinical program, including 3 interventional studies in epilepsy patients and a first-of-kind observational study in collaboration with The Epilepsy Study Consortium. We look forward to building on the encouraging preclinical and clinical data generated to date, with top line results from the first efficacy study expected in the first half of next year.

Switching to the upcoming readout this quarter, we remain on track to report top line results for the Phase II EMBOLD studies of relutrigine, or PRAX-562, in pediatric patients with developmental and epileptic encephalopathies. We're very excited about the upcoming readouts and the potential of relutrigine in SCN2A and 8A and also look forward to further exploring this pipeline and a molecule opportunity across a broad range of indications.

With our strong cash position, we are fully funded throughout several key readouts, which will continue to position Praxis at the forefront of precision medicines for CNS disorders.

Let me now spend a few more minutes on ulixa. The unmet needs for ET patients is undeniable, with millions of patients in the U.S. in need of a therapeutic option that allows them to perform daily activities without the impairment created by the condition. With such a large market opportunity, the ET landscape has been ready for innovation.

Ulixacaltamide is a unique and highly selective small molecule, inhibitor of T-type calcium channels designed to block abnormal neuronal burst firing, which should lead, as you've seen, and you're going to be looking into the new study, to improvements of ET symptoms in patients.

It has been only a short 9 months since we started the biggest and most comprehensive ET program conducted to date with Essential3 comprised of 2 simultaneous Phase III studies, including a 12-week parallel design and a 12-week randomized withdrawal.

Essential3 incorporates a decentralized design to reduce patient further, which we have been working for a while, together with certification of key parameters to maintain balance across groups and the implementation of a very comprehensive screening protocol to ensure suitable patients participate in this study.

We knew going in Essential3 that the proper endpoint had to be the mADL11, as we've discussed previously, and also the importance of putting in place the controls to minimize variability and placebo effect, and that was all done.

While we are confident about the design and the execution of the program, we are also cognizant of being the first in a space like essential tremor and the responsibilities that are bestowed upon us to leave no rock unturned in order to maximize the proven top success of ulixa.

With all of this in mind, we built in from the very beginning of this study, from the onset of planned interim analysis for the parallel group study, or study 1, in the Essential3 program. We have discussed this plan with the FDA, and we intend to complete the analysis in Q4 2024.

The base assumptions we've been using and we're going to continue to use at this point in time is that we would read out the study shortly thereafter. The strong participation we are seeing in Essential3 continues to highlight the significant unmet needs for new therapies in essential tremor, and we really look forward to fulfilling these needs and filing our planned NDA next year.

I'll now move to our highly differentiated epilepsy portfolio. beginning with PRAX-628. As a reminder, PRAX-628 is a next-generation functionally selective small molecule from our Cerebrum platform. 628 is currently being developed as a once-daily oral treatment for adults with epilepsy.

Building off these strong results seen to date with 628, both preclinically and clinically, we have started a comprehensive late-stage program in epilepsy, and we call this program ENERGY. ENERGY is comprised of 4 studies, aiming to build a strong base of patients for our trial, while generating multiple data points over the next 18 months to support the differentiated profile of PRAX-628.

We're very excited to be collaborating with The Epilepsy Study Consortium, a first-in-kind initiative, to characterize a very large group of epileptic patients and, amongst other things, assess the appropriateness of participation in clinical studies. This initiative is conducted under a clinical protocol called EMPOWER, which is expected to be up and running this quarter and to be active during the entire development program for PRAX-628.

RADIANT is the first of 3 planned efficacy and safety studies we expect to start in the coming months. RADIANT will enroll patients with either focal or generalized epilepsy who'll receive 628 for 8 weeks. Site engagement and recruitment initiatives are underway, and we plan to enroll up to 50 patients and expect top line results in the first half of 2025. RADIANT is expected to provide the important safety, PK and efficacy information about 628, and we are really looking forward to it.

POWER1 and 2 are our 12-week Phase II/III studies in patients with focal onset seizures. POWER1 is expected to start enrolling later this year, with results expected by the second half of 2025. We expect POWER2 to be initiated in the first half of next year, which we believe, together with POWER1, would generate a robust efficacy package for PRAX-628.

With that, I would now like to turn to our relutrigine program for DEEs, which are a group of severe epilepsy characterized by developmental delays with early onset. Relutrigine is a first-in-class small molecule and preferentially inhibit persistent sudden currents, which has been shown to be quite a key driver in uncontrolled seizures in multiple DEEs.

The preclinical and clinical data we reviewed before for relutrigine supports a differentiated profile in DEEs, particularly those without any effective and safe treatment available today. We look forward to the top line results from our proof-of-concept study EMBOLD this quarter. We have been particularly humbled by the severity of the patients in the study and the huge unmet needs they bring to the table for better therapies.

At the time of the readout, we expect to be able to share the efficacy and safety of the placebo-controlled part of this study as well as available data from the long-term extension portion as appropriate. We believe relutrigine has potential as a best-in-class option serving as a backbone therapy across multiple DEE indications and really look forward to discuss that further with you all in the near future.

Finally, I'd like to turn to elsunersen, or PRAX-222, our ASO designed to selectively decrease expression of SCN2A gene and directly targets the underlying cause of early onset seizures in SCNA2-DEE.

In the second quarter of this year, we initiated the first arm of the global registration study for elsunersen in Brazil, which is expected to be followed shortly by the expansion of the program in Europe and in the U.S. later this year. This study builds on the very encouraging data from Part 1 of EMBRAVE, where patients achieving significantly seizure reduction and significantly increase in seizure-free days, while being generally safe and well tolerated.

As we take all of the updates together, we anticipate all 4 programs to rapidly advance throughout late-stage development, with multiple regulatory filings expected in the next few years, which is incredibly exciting.

With that, let me now turn the call over to our Chief Financial Officer, Tim Kelly. Tim?

[Tim Kelly, executive]

Thanks, Marcio, and good morning, everybody. Thank you for joining today's call.

I'll provide here a quick summary on the financials for the quarter. In Q2, our operating expenses were $37.8 million with $27.3 million of that for R&D and the remaining $10.6 million for G&A. During the second quarter, Praxis spent $27.4 million in operating cash compared to $20.9 million in the first quarter of 2024, with the increase reflecting more activity for the Essential3 studies, while we continue to maintain a focus on optimizing working capital.

We ended Q2 with $433.8 million in cash, equivalents and marketable securities compared to $81 million of cash in December. The increase of $352.5 million is primarily due to net proceeds from Praxis January 2024 and April 2024 follow-on public offerings. Our cash supports a runway into 2027 and includes funding all studies that Marcio discussed today to their readout.

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

[Marcio Souza, executive]

Thank you, Tim. We're now going to open the call for Q&A. Thank you. Operator?

[Operator]

[Operator Instructions] And our first question coming from the line of Yasmeen Rahimi with Piper Sandler.

[Yasmeen Rahimi, analyst]

And congrats on kicking off the ENERGY program. Tim, a few questions. First one is you alluded to that, I guess, could you comment whether enrollment, I guess, it seems like it's still sort of finishing up, if you could quantify sort of where you are and the cadence of getting Essential done.

Second is you spoke about an interim analysis. Could you maybe talk about what this interim analysis you are referring to? Because it's maybe a new word that we just picked up on. I would love your thoughts on that, what that analysis is and what will be unveiled.

And then the third question is, could you maybe talk to us about, given that RADIANT will read out in the first half ahead of the POWER studies, how predictive is going to be the RADIANT study in terms of read-through to POWER1 and POWER2, given that it had maybe a more broader population and how you're thinking about enriching that group?

[Marcio Souza, executive]

Absolutely. Thanks for the questions. So on the first one, right, if you can -- as we look into our slides 8 in our corporate deck we posted this morning, you're going to see we're clearly maintaining the guidance that we had before. So it's by no mean a delay here introducing the interim analysis.

What I wanted to be clear here, which is going to segue to our second quarter, as we're looking for the study from the get-go from the very [ beginning ] on the prepared remarks, the possibility of adding an interim analysis, and we did. That was properly discussed and it's been the very first portion of the protocol, statistical analysis planned and so on, primarily for 2 reasons.

One, obviously, things can go better than we expect, number one; and two, things could happen along the way that might consider depending on the [indiscernible] for us to do this analysis.

Now in turn, nothing happened along the way, but we have to consider the pace of enrollments, type of patient, characteristics of the patient, apply the data. It's all looking exactly as we expected here. So that is a check, and there would not be a reason to conduct an interim.

But externally, there are factors that have been [indiscernible] and that might have influenced like the way we think. So the -- on the cost of [indiscernible] something is very small as it is the case here, but the upside is very large.

And if the case here, meaning if you were, for example, to exercise the ability to increase the sample size, in case just like a recent readout from another competitor program, seems like placebo is slightly higher than expected, not what we are seeing, but we remain more diligent here.

We might have the opportunity to do that because we have tremendous interest to the trial. That wouldn't be really a problem for us whatsoever to do that at point. And we continue to do the study. So a big insurance policy on one hand and not really an indicator that there is anything happening with other enrollments or the program itself.

On the other hand, it felt appropriate for us considering the responsibilities that we have right now to deliver this program, not only for all of our [indiscernible] at Praxis, for all the investors like you are representing here, but patients, right, that don't really have any other option in development now for them.

So when you put that all together, increasing the product of success of the overall program was a key driver, and we believe we're doing that by conducting this analysis. So that is on the second.

On RADIANT, so RADIANT is, I think, a phenomenal study to be conducting right now. It adds an intermediate readout for us, which obviously continue to build [excitement ] of 628, which generates data. So there are a couple of points, which lead to generate more.

One, again, continues to build the success we're seeing now with patients that have uncontrolled seizures, both with focal onset and generalized. But the second is we want to, and we believe that since we're accelerating pretty quickly to a potential NDA, not [ intended] far in the future, to continue to characterize PK in this population, which is not something fancy or something that we often discuss that needs to be done, but it should be [ done ] in conducting that on my study.

That's what operationally far easier is the second parameter and is our first foray on [indiscernible] patients who have generalized where we're going to get an even potential for our second indication here in the future. So understanding that as well.

All of that done in an incredibly efficient way, right? The excitement from all the investigators we talked to is incredibly high. I think everyone is really looking forward to having their [indiscernible] something edification as it looks [indiscernible] what it's going to be.

So it wasn't all [indiscernible] in between. Of course, we're going to learn things as well on this study. That's going to help [ buy our ] package. So when you look into a potential package for registration here, POWER1, POWER2, and whatever we learn from safety and exposure relationships and so on RADIANT should be that package in the near future. Sorry for the long answer there. And hopefully, I answered everything you asked.

[Operator]

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

[Joon Lee, analyst]

Congrats on the progress. And I think interim is a good -- it's part of good housekeeping. But if you do decide to resize the trial for any reader, that could potentially push out the time line for Study 1. With the randomized withdrawal trial, which I believe is Study 2, still readout by year-end, I don't think that there is an interim for Study 2, I believe. And I have a follow-up question.

[Marcio Souza, executive]

Yes. So thanks so much, Joon. So Study 1 and 2 now are [ slotted ] to read out together, right, as you know. We're still expecting to be the case as we do expect, as you properly [indiscernible] there the insurance is going to be a housekeeping exercise.

But in the case, which we're not expecting to happen, but it could happen, then we need to slightly increase the size of Study 1. Then they would be separated. We don't believe by a very large period of time because we do have sufficient patients.

We are not going to be closing the screening and pre-randomization work for the Study 1. It will be quite fast, if that happens. It was one of the motivations, to be honest, on our end, so we have enough patients that wouldn't be [indiscernible] and creates a significant cohort effects.

[Joon Lee, analyst]

Great. That's a fascinating set up there. The follow-up question is as we look forward to the relutrigine data in DEE, helps us with some -- help us set the bar for what you think is a good data and what -- from SCN2A and 8A, are you saying that the opportunity in 2A and 8A could be just the tip of the iceberg on future application? Can you elaborate on that a little bit? For example, what other types of DEE did you have in mind?

[Marcio Souza, executive]

Yes. No, that's -- and thanks for that. So we continue to monitor the progress here. We are really very, very close to that readout, right? Incredibly excited. But there are 2 things there that I mentioned on the prepared remarks, just going to want to bring back.

So one, those patients were far more severe than we originally expected. And I think that is quite interesting from the [indiscernible] to actually drive some relief for themselves, for their families, which is exciting for us. We guided before we're going to continue to guide at this point in time 20% to 30% seizure reduction. We think that would be quite phenomenal from the sample size we have, from the type of patients enrolled.

Of course, we want to see patients doing as well as possible. You might have caught as well the fact that you're going to have, in my view, a significant number of patients crossing the long-term extension. So we're going to be able to talk about what happens when they continue taking the drug and so on. So that is -- there.

Then you open, I would say, the horizon here, and through other DEEs amount for something like 300 genetically defined epilepsies at this point in time, right, it's incredible the growth that existed on understanding since the pioneers in this field, like [indiscernible] or Dave Goldstein and others started looking to this [indiscernible] and other folks.

But the use of very toxic, but it's too efficacious sodium channel modulators, it's pretty wide. So if you think nothing else but [indiscernible] patients trying to control [indiscernible] mechanism that gives them some relief, but they really can't because there are limitations on both efficacy and safety.

That alone, it is probably the largest opportunity in the DEE that anyone ever talked about. And as we look into that, what you're probably going to be hearing from us is a broader approach in terms of patients who have very severe uncontrolled and pediatric DEE because that is the key here, right? It's a very different manifestations. As they get older, probably not as severe as it is when they are young. That number is pretty big, not only from our market opportunity, but from an unmet need opportunity. And I think that that's what we're focusing on right now.

[Operator]

And our next question coming from the line of François Brisebois with Oppenheimer.

[François Brisebois, analyst]

So just first of all, so you mentioned the 20% to 30% seizure reduction would be great, especially with this size of a trial, but should we be expecting a p value here? I just want to make it clear for expectations into the data.

[Marcio Souza, executive]

Thanks for the question. The -- so we are like -- again, we keep guiding here we're going to continue for 20% to 30%. I think what I would like to see on top of that is the distribution of the patients, right? And I think we're going to be talking about that. There are things that are more common, like variable example in some of those patients. There are things that are purely uncommon, like significantly reduction, potential part periods without seizures and things like that. So we're kind of weeks away, I would say, since we guided for Q3. So I'm going to continue to look into that.

When you think about tolerability, they go to hypothesis on this study is that we would see a lot of issues with these patients. They are unknown for having very poor tolerability with any agents they take. And I can say because tolerability is not blinded, right? We're [indiscernible] for all the study. That is not the case.

We're seeing very good tolerability with this drug, which gives us even more encouragement on how it can be used and explored for controlled and uncontrolled case. So stay tuned. It's in our foot step. It's very close for us to be talking about this, so we're going to be having a fulsome discussion as the results are out.

[François Brisebois, analyst]

Okay. And then just in terms of the study design, just differences with others in terms of essential tremor, can you just help us understand maybe the differences and the thought process between doing parallel and randomized withdrawal? And just overall, just maybe going through the differences that make you feel comfortable with the readout -- or more comfortable than what others ran into here.

[Marcio Souza, executive]

Yes. So the thought from the get-go on the -- I will start with the randomized withdrawal here because I think it's quite interesting, right? The way drugs are used in the markets is a patient taking the drug. And if they respond, they stay on the drug. If they respond, they just continue.

The way -- and I know it sounds insanely odd what I just said, but it doesn't feel like when we have questions like this on how odd it is, then you go back to how you test the drugs, and you just assign them to groups that would never actually behave that way, right, like parallel groups and other designs.

So when we discuss with the agency, when we discussed internally, that was quite important to establish like what happened with these patients. They maybe remind everyone that patients with essential tremor tolerates anything. They are giving a lot of other potential therapies, and they may continue all of that. The terminal rate is like [indiscernible] of retention on treatment. So that was quite important.

Now that study, it's pretty straightforward in a sense that we sized that significantly higher than we believe we needed. So that's why we're continuing that. That's why from the beginning, we have our plans to do any potential adjustments with that.

The parallel group, the key [indiscernible] influence in that from the beginning is [indiscernible] has been many, many discussions in the fields. Essential tremor never had a pharmacological drug that is approved, which is a very comprehensive study and analysis of Essential1, if we understand the groups really well and we power the trial and conducted the trial based on those learnings.

Now as we move forward to a much larger study, I think what was important and continues to be important to understand how this heterogeneous group of patients, since there is not a one determinant of essential tremor behave when you expose them to a relatively long period of time, like 3 months now, and I look into what's happening in the study right now, it's pristinely done. It is done exactly the way we're expecting, and all the indicators as we're expecting.

But we still have that unknown of heterogeneous population that might influence things as likely one way or another. That's why we're planning that we are planning right now. This is a registrational package. And we want to make sure, as you heard in our disclosures as it is in our slide deck on our website, to file an NDA next year.

And to file that NDA, we need these studies to be [indiscernible] and that we're doing everything in our power to get the first pharmacologically approved treatments in recent decades for essential tremor patients. So that's how the program is designed.

[Operator]

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

[Yatin Suneja, analyst]

Just a couple of clarifications for me. So with regard to the interim analysis in Study 1, could you tell us what would be the sample size that will trigger it? So that's one. What exactly are you looking for? Is there a particular mADL11 delta you're shooting for there? And then is there an alpha loss there since you do an interim analysis? And what sort of an alpha loss? And then I have a follow-up on the other program.

[Marcio Souza, executive]

So the interim is based, and while I'm there, I'm going to give you the information point here. You have to, and I'm sure you, can believe that it has to be sufficient for the estimation of the entire study.

We are using a promising zone approach to understand where we are. So the reestimation one exists, right? It's just a reminder that it is not our base assumption. The base assumption is situation without reestimation. If reestimation happens, it's going to be based on the boundaries, the recommendation of the independent IDMC that we have. Now it's all within the range of things we believe we can randomize quite quickly to increase the probability of success of the final trial.

One of the constraints we've been working on and one of the reasons why we didn't discuss this before is final cohort enrollment is incredibly fast. So when you have a situation like that, the readout, the potential interim as we're doing in the final [indiscernible] are pretty close together. So we are considering that as well as we're completing the study.

[Yatin Suneja, analyst]

Okay. For the final analysis or, let's say, for this study,readout, is there -- what is clinically meaningful in terms of mADL, both from the absolute side and also on the placebo-adjusted delta?

[Marcio Souza, executive]

Yes. When you look back, most of the work, if not all the work that was [indiscernible] clinical meaningfulness follow the recent, like last year's, FDA guidance on patient-driven drug [ events ] and historical guidance in terms of how you anchor these endpoints.

Intensively, when you anchor the mADL to an unknown disability end-points like global impression, what you see is a perfect alignment between change on the ADL and change on the global impression.

It's actually quite obvious for us because when you talk to patients, they [indiscernible] to describe what will be important, [indiscernible] talk to physicians and you ask them what they would think to be important on their patients, they all describe the gain or maintenance of a function. When you go back to the ADL, that is one point.

When you transform that to mADL11, as is required on this study, that has obviously dropped below 1 point. This study is well powered beyond that. But that would be the large and proper answers. If we can properly drink from a cup, and now you can, I challenge anyone to tell me that that's not [indiscernible] to our patients. It's incredibly [indiscernible] that's a point or less.

But now what we are planning to see on this study is obviously more than that. But it's quite important as well that the proportion of patients gaining 1 point, 2 points, 3 points, whatever, are prefab. So it's not only a point estimation, but also like the proportion of that, and we're monitoring, of course, and we will continue to monitor and talk about that.

If you look into our corporate deck, we talked about the treatment of 3 points. We talked about proportion of patients that are there and so on. So it's very clear that this is going to be a quite meaningful treatment for patients with essential tremor, especially the ones that are with significant disability due to their conditions.

[Yatin Suneja, analyst]

Got it. Maybe one more multiple part, a classic sell-side question. So for the interim analysis, this is an efficacy analysis, not futility analysis; two how you will disclose or what exactly are you willing to disclose to us when this interim happened? And when exactly is this happening? Is it a Q3 event or a Q4 event?

[Marcio Souza, executive]

Yes, absolutely. It's currently scheduled to happen in Q4. Just as a reminder, the patients have to complete the whatever information points we determined. The data has to be claimed transferred to an external independent data monitoring committee and then the analysis should be [indiscernible]. So -- and coming back to us and so on. It will take a little while. That's why, therefore, the time line.

The -- what we intend to communicate on launching time is what we're going to do is a decision that is being held at that point in time with DNS. So the -- I'll argue the likely decision here is we will update all of you with the readout when the full readout for this study is going to happen.

And in the eventuality that we believe is appropriate, as recommended by the IDMC to increase the sample size, what is the increase, and we would be reading out that as well, which we believe [indiscernible] increase if that is to happen, we would have quite shortly thereafter.

[Operator]

And our next question coming from the line of Ritu Baral with TD Cowen.

[Ritu Baral, analyst]

I have got one last question on ulixa and then a bunch on 628. So for the Essential, the withdrawal study, I know that sometimes FDA imposes official or unofficial requirement on the initial response rate for those patients going in that are defined as responders before the actual withdrawal portion is conducted and analyzed.

Have you spoken to FDA around the design of the withdrawal study, specifically on that initial open-label responder rate, sort of what they're looking for, even if -- and if there is even a hard requirement or just a soft would like to have?

[Marcio Souza, executive]

Yes. No. Thanks, Ritu. The -- from the beginning as well, even actually from the Phase II, we have proposed a randomized one of the studies there, right? One of the parameters, as you wisely noted, there is the definition, right? We're going to randomize only stable or stable with another criteria and things like that.

And our proposal from the get-go and what's being implemented in Essential3 was that in the first 8 weeks they will be exposed to drug is a response criteria, bilateral response criteria, meaning the criteria increase and decrease is identical. If they cross their boundary, we're going to be disclosing shortly.

As you can imagine, that could influence some assessments. That's why we didn't disclose before. Then they can be randomized to stay on drug or to go on placebo for the following 4 weeks. If patients are not to meet the criteria at week 8, and maybe that is what we haven't really talked much before, they are moved into the long-term extension programmatically, right?

They don't know that they were excluded as the entire [ population ] remains blinded for the entire duration of the 12 weeks. So only responders are randomized after 8 weeks. And therefore, they are the only ones "at risk" of losing the effect when they are randomized to placebo.

[Ritu Baral, analyst]

But the original sort of open-label response rate going in, there was no criteria for what was required around that.

[Marcio Souza, executive]

They are all randomized under...

[Ritu Baral, analyst]

They're all blinded already. Okay.

[Marcio Souza, executive]

Yes. Correct.

[Ritu Baral, analyst]

Okay. Understood. Moving to 628 and the RADIANT studies. First of all, can we confirm that the RADIANT and POWER1, 2, those are placebo-controlled studies?

[Marcio Souza, executive]

Yes. So RADIANT is not placebo controlled. POWER1 and POWER2 are placebo controlled.

[Ritu Baral, analyst]

Got it. And then what doses are you using? Just given the very good safety that you've seen, what doses are you using in RADIANT and POWER2, the 628?

[Marcio Souza, executive]

Yes. So RADIANT, all patients are going to start at 30 milligrams. POWER1 and 2 [indiscernible] updated the schematics in our PowerPoint and our website as well. Patients will start at 20 milligrams for 6 weeks and then 30 milligrams for the -- for other 6 weeks. On POWER2, there is a lower dose as well just to fulfill potential requirements for lower dose exposure there.

The deal with RADIANT, there are more flexibility here as well. So maximum efficacy, which could be derived from day 1, but it's [indiscernible] for investigators to make potential recommendation for adjustments, adjust other drugs that cannot be done in the setting of a double-blinded study when you don't know if patients are on drug or which dose they are in because they could interfere.

So that is the idea. It's also as you heard on the previous comments, right, we have collected quite extensive samples from this study, so it becomes a lot easier to recruit them in general.

[Ritu Baral, analyst]

Is there a minimum percentage of generalized epilepsy or maximum percentage for generalized epilepsy that you have in mind for RADIANT? We're asking just because when we did our doc checks, some of our KOLs were particularly excited about the potential for 628 in this population.

[Marcio Souza, executive]

It was -- I'm glad you bring that up because one of the motivations actually for [ 628 ] include originally, we thought about only conducting [indiscernible], but there is a very, very clear excitement about 628 on the investigators in general.

When they look into highly translatable preclinical models across the board, I think what they are imagining, and there might be [indiscernible] for me at least, is even beyond what we are imagining, the potential of this drug, potential for seizure [indiscernible] and things like that, that I think we are humbled by [indiscernible] drug development in general.

So that is clearly a push. We do expect by the conversations we have with the sites that are going to be enrolling and the investigators, in general, they're going to follow the general proportion of patients in the clinic. So about 30% or so should be generalized and the reminder of that should be [indiscernible].

[Ritu Baral, analyst]

Got it, got it. And then final question. Other than the dosing, do you see in the design, are there any major differences between POWER1 and POWER2 of note?

[Marcio Souza, executive]

So at this point in time, there are no major difference. The POWER1, the reason why we are really pushing that ahead before POWER2 as well is, one, taking one study off the ground. Or in the case of RADIANT, it's obviously operationally simpler.

The second is there is overlap in terms of size, expected places we want to go for POWER2. And we wanted to make sure we're [indiscernible] on their way on the enrollments on POWER1 at the moment we start that, if not complete. So we wanted to stagger to give the maximum opportunity for patients to enroll on POWER1. That was the main motivation here.

[Operator]

And our next question coming from the line of Joel Beatty with Baird.

[Joel Beatty, analyst]

A couple on Essential3. The first is, what's the next update for us to expect from the Essential3 program? Would it be an announcement on the completion of the planned enrollment? Or would the next update be the implications from the interim analysis?

And then as a second question, has the data from Essential3 been able to be looked at on a blinded basis, perhaps to assess things like whether the variability of the data is in line with expectations?

[Marcio Souza, executive]

Joel, so I'll tackle the second question here first. So yes, we continuously look into the [ deep ] in a blinded fashion. And the variability is actually as expected, not lower in terms of the patients coming in #1 and then in the study [indiscernible] the randomization is actually lower -- sorry, is actually as expected. It's lower beforehand. So 30 stable patients coming in as expected patients during the study. So all systems are go and green there. That is not the motivation for the plans in trend to [indiscernible].

On the next update, we do expect to talk about when we are -- when we have completed all the next stage [indiscernible] program. And also we should see significant updates coming up soon, not only on enrollments, but on the initiation and completion of the interim analysis.

[Operator]

And our next question coming from the line of Ami Fadia with Needham.

[Ami Fadia, analyst]

Firstly, just a follow-up on 628. What is the gating factor for initiating a pivotal program for generalized epilepsy? And is RADIANT meant to inform the dose that you would study in that epilepsy type? And then I have one quick -- other quick follow-up.

[Marcio Souza, executive]

Yes. The motivation here for, including generalized, you might recall [indiscernible] is quite broadly [indiscernible]. So this is the first [indiscernible] what we're trying to look into is the, I would describe, as the terminal value of this model here, right?

So when we start with patients that are, I would say, struggling to respond, but likely to respond in our view, and that's the way we're thinking about RADIANT, [indiscernible] to understand whether or not we can really drive the efficacy of this drug.

Now [indiscernible] powering double-blind study, but really driving the potential maximum here. Obviously, there is safety collection here that would add to a safe database. That's quite an importance. But maybe even primarily, I keep going back there, but we don't want to throw out your study, keep collecting more and more PK samples from patients. And I know it sounds minimal, but [indiscernible] towards a potential NDA that becomes a quite important consideration as well.

And as we want to expand the program, right, after POWER1 or 2, it's very, very likely that we are running another study in generalized epilepsy. So we wanted to start getting some experience with that patient population. That was the motivation here.

I think the bonus to all of us, particularly our investors, is another milestone here and intermediate readouts before POWER1, which should obviously boost more confidence on the overall [indiscernible], particularly on our end, right? [indiscernible] this program with a very high confidence on the readouts.

[Ami Fadia, analyst]

Got it. That's quite helpful. With regards to PRAX-562, can you talk about how age and baseline severity impact how much seizure reduction we could expect to see? Also how could we -- how should we think about read through into other DEEs based on the data that you will share with us on the 2 DEEs subtypes?

And then maybe I'll just club it in here. A quick follow-up on ulixa. Is the interim analysis likely to drive a statistical penalty or not?

[Marcio Souza, executive]

Yes, sure. So we're looking to be involved on the upcoming readouts. I think we absolutely should look into this and how it extrapolates to other DEEs. The world of DEEs is being dominated by this [indiscernible], number one, and then two, by these buckets of unknown things that we call [indiscernible] most recent some instance.

But there are far more patients that are -- have no alternative. There was a reduction as little as it might look or not look, right, we're obviously not expecting for little reductions here. We expecting for significant reductions, will significantly change, one, their lives and their parents trajectory, but the second is their survival.

So we are absolutely sure that we're going to be talking during extrapolate the [indiscernible]. And let me get back to your first question about the age [indiscernible] burden there. [indiscernible] encephalopathies are disease of childhood, right? When you look into the patients that enrolled in our study, as you're going to see pretty soon, we're talking about pretty young kids, seizure burdens that are very, very high, disabilities that are quite prominent.

When you see gains there, as we told you would expect to see from these patients, is very meaningful because their body are still developing, their brains are still developing, and there's like a huge opportunity here to continue to help them throughout their lives.

It's exciting to see there, and we believe it's quite translatable to a very large number of DEEs that don't really have any opportunities, that have similar characteristics, young, high-seizure burden, very low ability to treat mostly because of safety and tolerability to drugs.

[Operator]

And our next question coming from the line of Douglas Tsao with H.C. Wainwright.

[Douglas Tsao, analyst]

Just maybe starting with RADIANT. I think given the PPR results, there was a lot of interest in terms of 628's effect in generalized epilepsy. I'm just curious, why not just do that study with generalized epilepsy patients?

And then also I'm just curious in terms of the dosing between RADIANT and the POWER studies. With POWER, you're starting at 20 milligrams for 6 weeks and then moving to 30. Why in RADIANT are you going directly to the 30 without sort of a titration period?

[Marcio Souza, executive]

Yes. Thanks, Doug. So we have a lot of flexibility on RADIANT to -- we go for this study, they're going to provide periodic updates on how things are going on that study to potentially actually [indiscernible] at a cohort. So we're not quite there yet, but your thought about why not do a generalized epilepsy study in 6 months, that's what we're going to be talking about. We're going to be talking about [indiscernible] the controlled study in generalized. I think, first, we wanted to understand the impact we could have, which we believe is going to be fairly large in both focal and generalized epilepsy.

The second question on the dose, I mentioned before, we want to drive the maximum potential efficacy here with [indiscernible] definition, the highest [indiscernible]. At the same time, we have far flexibility on RADIANT than we have on POWER1 and 2.

We do need to have some data on the different concentrations and the reduction in seizures. For example, we do believe that 20 milligrams for 6 weeks is going to be efficacious, and that would be sufficient. And that's going to be a quite important discussion decision with regulators once that is significant and then the 30.

So what is they start up? How do you actually treat patients? But after [indiscernible], if you see, let's call just [indiscernible] scenario planning, a very significant number [indiscernible] are seizure-free, then we might rethink what a labeling language could be in the near future.

So it's all complementary. I think as drug developers, we need to think about the piece of the puzzle that are going to allow for the best possible decision by the regulators and the physicians. And that's the -- that's how RADIANT plays a role here.

[Operator]

And our next question coming from the line of Kambiz Yazdi with Jefferies.

[Kambiz Yazdi, analyst]

For PRAX-628 in terms of local patient enrollment, how will you prioritize it between POWER1 and RADIANT? And then maybe you can go into more details of the POWER observational study?

And then for another program, elsunersen, what feedback did you receive from global regulators to initiate a pivotal study in Brazil and kind of what remains required to advance the program in the U.S. and Europe?

[Marcio Souza, executive]

Sure. Thanks, Kambiz. So POWER1 and RADIANT are not, I would say, competitive internally from a [indiscernible] or external. They just goes through very -- it's a much larger initiative. As you can imagine, POWER1, so all the administrative stuff that has to happen takes a little bit longer. It's a smaller number of sites for RADIANT. So that's part of that as well.

And the patient characteristics we might enrol is slightly different as well. So we were trying to actually triple our [indiscernible] to be perfectly honest or make [indiscernible] the both studies recruit quite excellently, as we expect to. So again, no competitiveness there whatsoever.

I think your second question about elsunersen, we do have, obviously, a full feedback from Brazil. We're able to start the study there. I believe that cohort is going to be quite complementary to the initiatives that we are having outside of the U.S.

We do have some preliminary [indiscernible] to be final soon from Europe as well, which are [indiscernible] aligns with how we are thinking about that [indiscernible] moving, and that's why we guided for more global parts, including Euro part [indiscernible] that starts later this year.and in the similar process with the FDA.

We know it's a complex program. We have multiple variables here. The most important of them is just how severe those patients are. So we're taking one step at a time on that program.

[Operator]

I'm showing no further questions in the queue at this time. I will now turn the call back over to Marcio De'Souza for any closing remarks.

[Marcio Souza, executive]

Thanks, everyone. I sincerely appreciate everyone joining the call and all the questions, having quite importantly as well the support for Praxis and all the patients we serve.

As you heard at the beginning, we do there for more. And oftentimes, that materialize on actually looking ourselves in the mirror and seeing what is best for the patients we serve. In the case of this call, it is really delivering successful studies for patients with essential tremor with ulixacaltamide hydrochloride as we will later this year. I hope everyone is as excited as I am of the upcoming results.

And just a reminder, in a few short weeks before the end of the quarter, we're going to be talking about our readout for our previous 562, relutrigine now as we're calling, which brings a quite important upside for all of us in terms of -- from an investor perspective.

But most importantly, SCN2A, SCN8A have no treatments, either available, approved or in development and are at the brink of being potentially approved. So to have the discussion, to have that coming up in a matter of weeks in front of us is quite exciting.

And then without saying on how excited we all are by the number of questions in today's call for 628. 628 is moving at lightning speed, as you can all see. I have worked in many programs in my life. I haven't seen as much excitement about a program from the investigators' perspective as we see with 628. And we are excited on not only getting that to the clinic potentially in the next few years, bringing that to market, revolutionizing the way epilepsy is treated.

So thank you, again, for the support. Look forward to having follow-up calls with you, and we'll see you soon.

[Operator]

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.