Praxis Precision Medicines, Inc.

Good day. Thank you for standing by. Welcome to the Practice Physician Medicine second quarter 2024 Corporate Update Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automatic message advising your hand is raised. 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.

Good morning, and welcome to Praxis Precision Medicine's second quarter 2024 financial results and business update conference call. This call is being webcast live and can be accessed on the investor 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 timelines, and financial projections. While these forward-looking statements represent Praxis's views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking on an obligation to do so. Please refer to Praxis's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Marcio Sousa, 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.

Thank you, good morning, and welcome to the PRAXIS second quarter 2024 conference call. PRAXIS is driven by our mission to dare for 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. We set PRAXIS in a position to have up to four programs in our registration phase by 2025. We continue to successfully drive our lead clinical program, ulexacultamide, towards registration, including the execution of our Pivotal Essential III trials in essential tremor, which expect the top-line results later this year. Additionally, following the positive VPR results in PRAC 628, we have designed a comprehensive clinical program, including three 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 redoubt this quarter, we remain on track to report top-line results for the Phase II and both studies of relitrogen, or Prax562, in pediatric patients with developmental and epileptic encephalopathies. We're very excited about the upcoming readouts and the potential of relitrogen in SCN2A and 8A. We also look forward to exploring this pipeline and molecule opportunity across a broad range of indications. With our strong cash position, we're fully funded throughout several key readouts, which will continue to position Praxis at the forefront of precision medicine for CNS disorders. Let me now spend a few more minutes on Ulexa. The unmet need 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. Ulexacultamide is a unique and highly selective small molecule inhibitor of T-type calcium channels designed to block abnormal neuronal burst firings. 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 nine months since we started the biggest and most comprehensive ET program conducted to date with Essential 3, comprised of two simultaneous Phase 3 studies, including a 12-week parallel design and a 12-week randomized withdrawal one. Essential 3 incorporates a decentralized design to reduce patient burden, which has been working super well, together with stratification of key parameters to maintain balance across groups, and the implementation of a very comprehensive screening protocol to ensure suitable patients participate in the study. We knew going in Essential 3 that the proper endpoint had to be the MA-DL11, as we 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're confident about the design and the execution of the program, we're 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 provenance of success of ELIXA. With all of this in mind, We built in from the very beginning of the study, from the onset, a planned interim analysis for the parallel group study, or study one in the Essential 3 program. We have discussed this plan with the FDA, and we intend to complete the analysis in Q4 2024. The base assumption 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 Essential 3 continues to highlight the significant termed needs for new therapies in essential tremor, and we really look forward to fulfilling these needs and filing our plans NDA next year. I'll now move to our highly differentiated deplepsy portfolio, beginning with PRAC628. As a reminder, PRAC628 is a next-generation, functionally selected small molecule from our CERBRO platform. 628 is currently being developed as a once-a-day oral treatment for adults with epilepsy. Building up these strong results into 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 four 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 BRAC628. We're very excited to be collaborating with the Epilepsy Study Consortium in 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 PRAC 628. RADIAN is the first of three planned efficacy and safety studies we expect to start in the coming months. RADIAN will enroll patients with either focal or generalized epilepsy who receive 628 for eight 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. Radiance is expected to provide important safety, PK, and efficacy information about sex weight, and we're really looking forward to it. Power 1 and 2 are our 12-week Phase 2-3 studies in patients with focal onset seizures. Power 1 is expected to start enrolling later this year, with results expected by the second half of 2025. We expect Power 2 to be initiated in the first half of next year, which we believe, together with Power 1, will generate a robust efficacy package for PRAX-X2H. With that, I'll now like to turn to our relutrigine program for GEs, which are a group of severe epilepsy characterized by developmental delays with early onset. Relutrigine is a first-in-class small molecule and preferentially inhibits persistent sorting occurrence which has been shown to be quite a key driver in uncontrolled seizures in multiple GEs. The preclinical and clinical data we reviewed before for relutrigine supports a differentiated profile in GEs, particularly those without any effective NSAID traits available today. We look forward to the top-line results from our proof-of-concept study and BALDS this quarter. We have been particularly humbled by the severity of the patients in the study and the urgent 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 control part of the 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 DE indications, and really look forward to discuss that further with you all in the near future. Finally, I'd like to turn to Alzheimer's or PRAX222, our ASO designed to selectively decrease expression of SCN2A genes and directly target the underlying cause of early onset seizures in SCN2A DE. In the second quarter of this year, we initiated the first arm of the global registration study for Alzheimer's 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 one of INBRAVE, 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 four 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?

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 Essential 3 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 reports 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.

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

Thank you. Operator? Ladies and gentlemen, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 1-1 again Please stand by while we compile the Q&A roster. Now, first question coming from the lineup, Yasmin Rahimi with 5% Learning. Your line is open.

Good morning, team, and congrats on kicking off the energy program. Team, 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 in the cadence on getting essential done. Second is, you spoke about an interim analysis. Could you maybe talk about what this interim analysis is referring to? Because it's maybe a new word that we just picked up on, 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 RADIAN will read out in the first half ahead of the power studies, how predictive is going to be the RADIAN study in terms of read-through to power one and power two, given that it has maybe a more broader population and how you're thinking about enriching that group?

Absolutely. Thanks for the questions. So on the first one, right, if you can, as we look into our slides, like eight 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 like a delay here introducing the Internet analysis. What I wanted to be clear here, which is going to segue to our second question, As we're looking for the study from the get-go, from the very beginning on the prepared remarks, the possibility of adding an in-train analysis, and we did. That was properly discussed in the very first portion of the protocol, statistical analysis plan, and so on, primarily for two 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 time for us to do this analysis. Now, in turn, nothing happened along the way. We'll consider pace of enrollment, 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 that would not be a reason to conduct But externally, there are factors that being and that might have influence like the way we think. So the, when the costs of something is very small, as it is the case here, but the upsides is very large, as is 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 competitive program, seems like placebo is slightly higher than expected. Not what we are seeing, but we remain humble and diligent here. We might have to do that because we have tremendous interest in the trial. That wouldn't be really a problem for us whatsoever to do that at points. It continues as they study. So a big insurance policy on one end, and not really an indicator that there is anything happening with either the 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 us at Praxis or 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 probability 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 Radiance, so Radiance is, I think, a phenomenal study to be conducting right now. It adds an intermediate readout for us, which obviously continues to build excitement of 6 to 8, to generate data. There are a couple of points to generate more. One, again, continue to build the success we're seeing now with patients that have non-controlled 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 NGA, not in that far in the future to continue to characterize PK in this population, which is not something fancy or that we often discuss that needs to be done, but needs to be done. And conducting that on my study, that is operationally far easier is the second parameter. And it's our first foray on patients with generalized where we're going to get like an even potential for a 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 really looking forward to having their something as efficacious as it looks six to eight is going to be. So it wasn't all in between. Of course, you're going to learn things. as well on this study that is going to help the entire package. So when you look into a potential package for registration here, power one, power two, and whatever we learned from safety and exposure relationships and so on on radiance should be that package in the near future. Sorry for the long answer there, and hopefully I answered everything you asked.

That was great. Thank you, Marcio. I'll jump back into the queue. Thanks, Yas.

Thank you. And our next question coming from the lineup, Jun Lee with Truist, your line is open.

Hey, congrats on the progress and thanks for taking our questions. And I think interim is a good, you know, it's part of good housekeeping. But if you do decide to resize the trial for any reason, it could potentially push out the timeline for study one. With the randomized withdrawal trial, which I believe is study two, still read out by year end, I don't think that there's an interim for study two, I believe. And I have a follow-up question.

Thank you. Yeah. So thanks so much, Jim. So study one and study two, now are slotted to readouts together, right, as you know. We're still expecting to be the case, as we do expect, as you properly were there, the insurance is just going to be a housekeeping exercise. But in the case, which we're not expecting to happen, but it could happen, that 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 who are not going to be closing the screening and pre-randomization work for the study one. It would be quite fast if that happened. One of the motivations, to be honest, on our end, is we have enough patients that wouldn't be a delay and creates a significant cohort effect.

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

Yeah, 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 two things there that I mentioned on the prepared remarks I just 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 accuracy 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 patient in the row. 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 the issue there. Then when you open, I would say, the horizon here and look to other Gs that amount for something like three hundredths genetically defined epilepsies at this point in time, right? Like, incredible the growth that existed on understanding since the pioneers on this field, like Steve Petro at the Goldstein and others, started, like, looking into this in detail, and Sam and other folks. But the use of fairly toxic, but it's too efficacious, sodium channel modulators is pretty wide. So, if you think nothing else but like patients trying to control 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 TE that anyone ever talked about. As we look into that, what you're probably going to be hearing from us, it's a broader approach in terms of patients who have very severe uncontrolled and pediatric ID, because that is the key here, right? So very different manifestations. They get older, probably not as severe as when they are young. That number is pretty big. not only from our market opportunities, but from our unmet needs opportunities.

And I think that that's what we're focusing on right now. Taking our questions. Thank you.

Thank you. And our next question coming from the line-up. with Oppenheimer. Your line is open.

Hi. Thanks for taking the questions. 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? Just want to make it clear for expectations into the data.

Yeah, so thanks, Alfred, for the question. So we are like, again, we keep guiding here. We're going to continue to 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. Like, there are things that are more common, like variable, for example, in some of those patients. There are things that are probably uncommon, like significantly reduction, potential part periods, like without seizures, and things like that. So we're kind of weeks away, I would say, since we guided 4Q3. So I'm going to continue to look into that. When you think about tolerability, the go-to hypothesis on this study is that we would see a lot of issues with these patients. They are known for having very poor tolerability with any agents they take. And I can say, because tolerability is not blinded, right? After all this study, that is not the case. they'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 now our footstep. 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.

Okay, thanks. And then just in terms of the study design, just differences with others in terms of essential tremor, can you just help us understand, you know, maybe the differences in 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. Thank you.

Yeah. So the thoughts from the gap go on the, I always start with the randomized drug here because I think it's quite interesting, right? The way drugs are used in the market is a patient takes a drug, and if they respond, they stay on the drug, and if they don't respond, they discontinue. 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 obvious it is. Then you go back to how you test 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 discussed with the agency, when we discussed internally, that was quite important to establish, like, what happened with these patients. It maybe reminds everyone that patients with essential trauma don't tolerate anything. they're giving like a lot of other potential therapies and they continue all of them. Like the terminal rate is like 50% of retention on treatment. So that was quite important. Now that study is pretty straightforward in a sense that we size that significantly higher than we believe we need. So that's why we continue that. That's why from the beginning we never planned to do any potential adjustments with that. The parallel group, The key part of influencing that from the beginning is, as being many, many discussions in the fields, essential tremor never had pharmacological treatments approved. We did a very comprehensive study and analysis of essential one. If we understand the groups really well, and we powered the trial and conducted a trial based on those learnings. As we move forward to a much larger study, I think it was important and continues to be important to understand how this heterogeneous group of patients, since there's not a one determinant of essential tremor, behave when you expose them to a relatively long period of time, like three months now. And I look into what's happening in the study right now. It's presumably done, and it's done exactly the way we're expecting. all the indicators as we're expecting. But we still have that unknown of Virginia's population that might influence things as likely one way or another. That's why we're planning the way 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 and our website, to file an NDA next year. And to file that NGA, we need the studies to be done. 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 project was designed.

Thank you. And our next question, coming from the lineup. with Guggenheim .

Hey, guys. Thank you for taking my question. Just a couple clarifications for me. So with regard to the interim analysis in study one, 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 M8811 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.

So the interim is based, and while I'm not going to give you the information points here, you have to, and I'm sure you do, believe that it has to be sufficient for the estimation of the entire study. We are using like a promising zone approach to understand where we are. So the re-estimation one exists, right? It's just a reminder that not our base assumption. The base assumption is evaluation without re-estimation. Re-estimation 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, like, 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 redial potential entrant, as we're doing, and the final cohort are pretty close together. So, we are considering that as well as work on this study.

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

Yeah.

When you look back, most of the work, if not all of the work, that was done for clinical meaningfulness followed the recent, like last year's, FDA guidance on patient-driven drug dependence and historical guidance in terms of how you anchor these endpoints. Intrinsically, when you anchor the MATL to unknown, like, disability endpoints, like global impression, what you see is a perfect alignment between chains on the ATL on the global impression. It's actually quite obvious for us because when you talk to patients and you ask them to describe what would be important, 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 ATL, that is one point. When you transform that to the MATL11, that is required on this study, that is obviously dropped below one point. This study is well-powered beyond that, but that would be the logical and proper answer is, if we can drink properly from a cup, and now you can, I challenge anyone to tell me that that's not true to a patient. It's incredibly mean. That's a point or less. 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 one points, two points, three 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're going to continue to talk about that. If you look into our corporate deck, we talk about three points. We talk about like 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 like with significant disability due to their condition.

All right. Maybe one more multiple part, like a classic cell site question. So for the interim analysis, this is an efficacy analysis, not futility analysis, to how you will disclose or what exactly are you willing to disclose to us when this interim happens and when exactly is this happening? Is it a Q3 event or a Q4 event? Thank you so much.

Yeah, absolutely. It's currently scheduled to happen in Q4. Like, just as a reminder, right, patients have to complete the whatever information point We determine that the data has to be claimed, transferred to an external independent data monitoring committee, and then the analysis should be conducted, and coming back to us, and so on. It takes a little while. That's why, therefore, the timeline. What we intend to commit at this point in time is what we're going to do. It's a decision that is being made. held at that point in time within it. So I'll argue the likely decision here is we would update all of you with the readout when the full readout for the 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, Evelyn, increase. If that is to happen, we would have quite shortly.

Thank you.

And our next question coming from the line of Ritu Barrow with TD Cowan. Your line is open.

Good morning, guys. Thanks for taking the question. I have got one last question on ELIXA and then a bunch on 628. So, for the essential, the withdrawal study, I know that sometimes FDA imposes an 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, and if there is even a hard requirement or just a soft would like to have?

Yeah, no, thanks, Ritu. From the beginning as well, even actually from the age two, we had proposed a randomized one of the studies there. All right, parameters, as you wisely noted, there is a definition, right, like we're going to randomize only stables or stable with another criteria and things like that. And our proposal from the GAFCO and what's being implemented in Essential 3 was that in the first eight weeks, they would be exposed to drug with a response criteria. bilateral response criteria, meaning the criteria for increase and decrease is identical. If they cross that boundary, they'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 four weeks. If patients are not to meet the criteria at week eight, and maybe that is what we haven't really talked much before, we are moved into the long-term extension. Programmatically, right, they don't know that they were excluded as the entire system remains blinded for the entire duration of the 12 weeks. So only responders are randomized after eight weeks. And therefore, they are the only ones, quote unquote, at risk of losing the effect when they are randomized to placebo.

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

They are all randomized.

They're all blinded already. Okay.

Yes.

Correct. Okay. Understood. Moving to 628 and the radiance studies, first of all, can we confirm that the radiance and power 1, 2, those are placebo-controlled studies?

Yeah. So radiance is not placebo-controlled. Power 1 and power 2 are placebo-controlled.

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 radiance and power 2 of 628? Yeah.

So Radiant, all patients are going to start at 30 milligrams. Power 1 and 2 updated the schematics in our PowerPoint and our website as well. Patients will start at 20 milligrams for six weeks and then 30 milligrams for the four other six weeks. On Power 2, there's a lower dose as well just to fulfill potential requirements for a lower-dose exposure there. The idea with radiance, there are more flexibilities here as well, so maximum efficacy should be derived from day one, but it's easier for investigators to make potential recommendations 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 drugs or which dose they are in because that could interfere. So that is the idea. It's also, as you heard on the previous comments, right, we were collecting more extensive samples from this, so it becomes a lot easier to recruit them in general.

Is there a minimum percentage of generalized epilepsy or maximum percentage of 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.

I'm glad you bring that up because one of the motivations, actually, include originally we thought about only conducting for onset, but that is a very, very clear excitement about 628 on the investigators in general. When they look into highly translatable preclinical models across the boards, people they are imagining, and that might be a for me at least, is even beyond what we are imagining of this drug. potential for seizure from the board and things like that that I think we're humbled by and about drug developments in general. So that is clearly a push. We do expect by the conversations we had with the sites that are going to be rolling and the investigators in general that are going to follow the general proportion of patients in the clinic. So about 30% or so should be generalized in the A reminder of that should be focal.

Got it. Got it. And then final question. Thanks for your patience. Other than the dosing, do you see in the design, are there any major differences between power one and power two of note?

So at this point in time, there are no major difference. The power one, the reason why we are really pushing that ahead before Power 2 as well, is one, taking one study off the ground, or in the case of RAID 1, it's obviously operationally simpler. The second is that it's overlap in terms of sites, expected places we want to go for 2, and we wanted to make sure we're on the way on the enrollments on Power 1. At the moment, we start that. It's not complete. So we wanted to stagger to give the maximum opportunity for patients to enroll on Power One. That was the main motivation here.

Understood. Thanks for taking all the questions.

Of course. Our pleasure.

Thank you. Our next question coming from the lineup. Joel Vita with Baird. Your line is open.

Hi, thanks for taking the questions. A couple on Essential 3. The first is, what's the next update for us to expect from the Essential 3 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 Essential 3 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?

Yeah. Hey, Joe. So I'll tackle the second question here first. So, yes, we continuously look into the data in a blinded fashion. And I'll tell you the variability is actually as expected, not lower, in terms of the patients coming in, number one, and then in the studies, the randomization is actually lower. Sorry, it's actually as expected, lower beforehand. Very stable patients coming in, as expected patients during the study. So all systems are green there. That is not the motivation for the plans entering to do. On the next update, we do have to talk about when we have completed all the next stages of the program. So you should see a signature. updates coming up soon, not only on the romance, but on the initiation and completion of the internet analysis.

Great, thank you.

Thank you. And our next question coming from the lineup. Amit Bhatia with Needham. Elon is open.

Hi, good morning. Thanks for taking my questions. 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 or two other quick follow-ups.

Yes. The motivation here for including generalized, you might recall,

of 628 quite broadly. So this is the first.

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 RADIAN. to understand whether or not we can really drive the efficacy of this drug. Not what we were powering, double-blind study, but really driving the potential maximum here. Obviously, that safety collection here that would add to the safety database, that's quite an importance. But maybe even primarily, I keep going back there, but we don't want to, throughout your study, keep, like, collecting more and more PK samples from patients. And I know it sounds minimal, but as we're accelerating towards a potential NGA, that becomes a quite important consideration as well. And as we want to expand the program, right, after PowerWare 2, very, very likely we'll be 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 an intermediate like readouts before Power One, which should obviously give more confidence on the overall product, particularly on our end, right? on this program with a very high confidence on the results.

Got it. That's quite helpful. With regards to PRAX-562, can you talk about how age and baseline severity impacts how much seizure reduction we could expect to see? Also, how should we think about read through into other DEEs based on the data that you will share with us on the two DEE subtypes. And then maybe I'll just plug it in here, a quick follow-up on Alexa. Is the interim analysis likely to drive a statistical penalty or not? Thank you.

Yeah, sure. So we're looking to involve in the upcoming results I think we absolutely should look into this and how it extrapolates to other Gs. The word of G is being dominated by this, by terapia, number one, and then two, by these buckets of unknown things that we call OGS or lenogastoid most recently, some instance. But there are far more patients. that have no alternative, that was a reduction as little as it might look or not look, right, we're obviously not expecting for little reductions here, we're expecting for significant reductions, would significantly change, one, their lives and their parents' trajectory, but the second is their survival. So we absolutely should, and we're going to be talking during the extrapolate, not beyond that. me back to our first questions about the age, seizure burden there. I develop encephalopathies or septic encephalopathies are disease of childhood, right? When you look into the patients that enroll in our study, as you're going to see pretty soon, we're talking about pretty young kids. Seizure burdens are very, very high. Disabilities that are quite prominent. When you see gains there, as we told you to see from these patients, that is incredibly meaningful because their bodies are still developing, they're developing, and there's like a huge opportunity here to continue to help them throughout their lives. It's exciting to see that, and we believe it's quite translatable to a very large number of Gs that don't really have any opportunity, that have similar characteristics, young, high seizure burden, very low ability to treat, mostly because of safety and tolerability of drugs.

Thank you. And our next question coming from the line of Doug Lester with HC Renberg. The line is open.

Hi, good morning. Thanks for taking the questions. Just maybe starting with RADIANT. You know, I think, you know, 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 six weeks and then moving to 30. Why in Radiant are you going directly to the 30s? without sort of a tight situation period. Thank you.

Thanks, Doc. We have a lot of flexibility on radiance as we go through the study. We're going to provide periodic updates on how things are going on that study to potentially actually spend at a cohort. So we're not quite there, but your thought about why not just run a generalized epilepsy In six months, that's what we're going to be talking about. We're going to be talking about starting that 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, which definition, the highest concentration. At the same time, we have far more flexibility on radian than we have on power 1 and 2. We do need to derive some data on the different concentrations and the reduction in seizures. For example, we do believe that 20 milligrams for six weeks is going to be efficacious, and that's sufficient. And that's going to be a quite important discussion decision with regulators once that is significant and then the 30. So what did they start though? How do you actually treat patients? But after Radiant, if you see, let's call just for scenario planning, a very significant unnumbered seizure freedom, then we might have to 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's going to allow for the best possible decision by the regulators and the physicians. And that's how RADIA plays a role here.

Thank you. And our next question, coming from the lineup. with Jeffrey . Good morning, Payne.

For PRAC 628, in terms of focal patient enrollment, how will you prioritize it between Power One and RADIANT? And then maybe you can go into more details of the Empower Observational Study. And then for another program, ELSA-NURSEN, 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? Thank you.

Sure. Thanks, Kevin. So Power One and Radiant are not, I would say, competitive internally from a reverse form or external. They just go through a much larger initiative, as you can imagine, Power One. So all the administrative stuff that has to happen takes a little bit longer. It's a smaller number of sites. for radiance, so that's part of that as well. And the patient characteristics dividing row is slightly different as well. So we were trying to actually trip over our results, we're going to be perfectly honest, on making sure that both studies recruits quite excellently as we expect to. So again, no competitiveness there whatsoever. I think you are Second question about nursing, we do have obviously full feedback from Brazil. We were 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 US. We do have some preliminary and should be final soon from Europe as well, which are aligns with how we are thinking about this, be moving, and that's why we guided for more global parts, including neural part, starting later this year, and in the similar process with the FTA. We know it's a complex program with, like, 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.

Thank you. Now I'm showing no further questions on the queue at this time. We'll now turn the call back over to Marcio Sousa for any closing remarks.

Thanks, everyone. Sincerely appreciate it for joining the call and all the questions. Having quite importantly as well the supports for Praxis and all the patients we serve. As you heard at the beginning, we do there for more, and oftentimes that materializes on actually looking at ourselves in the mirror and seeing what is best for the patients we serve. In the case of this call, it's really delivering successful studies for patients with essential tremor, with Bulexa-cultamide hydrochloric, as we will later this year. I hope everyone is as excited as I am. of the upcoming readouts. 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. We're liturging 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, SN2A, SN8A, have no treatments either available, approved, or in development that are at the brink of being potentially approved. So to have that 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 of 628s. 628s is moving at lightning speeds. 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 investigator's perspective as we see with six to eight. And we're excited on not only getting that to the clinic, but potentially in the next few years bringing it to the market and revolutionizing the way epilepsy is treated. So again, for the support, look forward to having follow-up calls with

And we'll see you soon.

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