Praxis Precision Medicines Inc (PRAX) 2024 Q2 法說會逐字稿

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.

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 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 meeting 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 practices used 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 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.

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 which set Praxis in a position to have up to four programs in our 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 expect a topline results later this year.

Additionally, following the positive PPR results in PRAX-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 topline 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 topline results for the Phase 2 EMBOLD Study 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 SCN8A.

We also look forward to further exploring this pipeline and the 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 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 US 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 birth 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 nine months since we started the biggest and most comprehensive ET program conducted to-date with Essential3, comprised of two simultaneous Phase 3 studies, including a 12-week parallel design and a 12-week randomized withdrawal one. Essential3 incorporates a decentralized design to reduce patient burden, which has been working super well, 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 the study.

We knew, going in Essential3 that the proper endpoint had to be the mADL11, 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 are 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 program top success of ulixa.

With all of this in mind, we built in, from the very beginning of the study from the onset of plans, raining 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 assumption we've been using and are 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 plan's 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 selected small molecule from our cerebral platform. 628 is currently being developed as a once-daily oral treatment for adults with epilepsy. Building up these strong results into date with 628 both pre-clinically 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 PRAX-628. 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 epilepsy 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 three plan's efficacy and safety studies we expect to start in the coming months. RADIANT will enroll patients with either focal or generalized epilepsy who receive 628 for eight weeks. Site engagements and recruitment initiatives are underway, and we plan to enroll up to 50 patients and expect topline results in the first half of 2025. RADIANT is expected to provide important safety, PK and efficacy information about 628, and we're really looking forward to it.

POWER1 and POWER2 are our 12-week Phase 2/3 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, will generate a robust efficacy package for PRAX-628.

With that, I'll 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 inhibits persistent sodium 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 insight to it available today.

We look forward to the topline result from our proof-of-concept study EMBOLD. 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 DEE indication, 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 target the underlying cause of early onset seizures in SCN2A 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 US 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 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 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 to $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. Operator?

Thank you. (Operator Instructions) Yasmeen Rahimi, Piper Sandler.

Hi. Good morning, team, and congrats on kicking off the ENERGY program. Team, few questions, first one, and 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 of getting Essential done?

Second is, you spoke about an interim analysis. Could you maybe talk about what this interim analysis is, you're referring to? Because this may be a new word that we just picked up on, would love your thoughts on what that analysis is and when it 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 has maybe a more broader population and how you're thinking about enriching that group?

Absolutely. Good morning, Yas, thanks for the questions. So on the first one, if you can, as we look into our Slide 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 means like a delay here introducing the interim analysis.

What I wanted to be clear here was going to segue to our second question. As we're looking for the study from the get-go, from the very beginning, we mentioned on the prepared remarks, we considered the possibility of adding an interim 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 that, for us to do this analysis now.

And third, nothing happened along the way. Like we'll considered phase of enrollment, type of patient, characteristics of the patient, provide 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 happening and that might have influenced the way we think. So when the cost of (technical difficulty) something is very small, as it is the case here, but the upsides is very large, as it 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 the opportunity 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, and continue to 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 end felt appropriate for us, considering the responsibilities that we have right now to deliver this program, not only for all of us at Praxis, for all the investors, like you are representing here, but patients, right, that don't really have any other option in development right 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 are 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 continues to build excitement of 628, to generate data. There are a couple of points to generate more. One, again, continues 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 NDA, not then 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 it needs to be done.

Conducting that on the 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 is really looking forward to having there something as efficacious as it looks like it's going to be. So it was an open door in between. Of course, we're going to learn things as well on this study that is going to help [entire] package.

So when you look into a potential package for registration here, POWER1, POWER2, and whatever we learned from safety and exposure relationships and so on. And RADIANT should be in that package in the near future. Sorry for the long answer there. And hopefully I answered everything you asked.

Joon Lee, Truist.

Oh, yes, congrats on the progress, and thanks for taking our questions. I think interim is part of good housekeeping, but if you do decide to resize the trial for any reason, that could potentially push out the timeline for Study 1. With the randomized withdrawal trial, which I believe is Study 2, still read out by year-end, I don't think that there is an interim for Study 2, I believe. And I have a follow-up question. Thank you.

Yeah, so thanks so much, Joon. So Study 1 and Study 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 know there, the interim 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 Study 1 will be quite fast if that happens. That's one of the motivations, to be honest, on our end, is we have enough patients that wouldn't be a delay and create a significant cohort effect.

Great, that's a fascinating setup there. The follow-up question is, as we look forward to the relutrigine data in DEE, help us set some bar for what you think is a good data from SCN2A and SCN8A and are you say that 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 DEE did you have in mind? Thank you.

Yeah, no, and thanks for that. 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, 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 [epilepsy] 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 you enroll. 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 when you open, I would say, the horizon here, and to other, the amount for something like 300 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 Petrou and David Goldstein and others started looking into this in detail and Sam and other folks. But the use of fairly toxic, but it's still efficacious, sodium channel modulators, is pretty wide.

So if you think nothing else but the case, like patients trying to control the 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 DEE that anyone ever talked about. And 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 DEE because that is the key here, right? That's a very different manifestation, as they get older probably not as severe as when they are young.

That number is pretty big, not only from a market opportunity, but from unmet needs opportunity, and I think that's what we're focusing on right now.

Francois Brisebois, Oppenheimer.

Hi. Thanks Franc for the questions. So just, first of all, 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.

Yeah, so thanks for the question. P, so we are, like, again, we're guiding 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 samples in some of those patients. There are things that are incredibly 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, 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, for all these 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 a 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, 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 get-go, and I'll start with the randomized withdrawal 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, 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 patients like this and 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 tremor don't tolerate anything. They are given like a lot of other potential therapies and they continue all of them. Like the terminal rate is like 75% of retention on treatment. So that was quite important.

Now that is study, it's pretty straightforward in a sense that we sized that significantly higher than we believe we need. So that's why we're continuing that. And that's why from the beginning, we never planned to do any potential adjustments with that.

The parallel group, the key for influencing that from the beginning is, there's been many, many discussions in the fields. Essential Tremor never had pharmacological drug approvals. We did a very comprehensive study and analysis of Essential1. If we understand the groups really well and we powered a trial and conducted a trial based on those learnings, now, as we move forward to a much larger study, I think what's 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 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 is 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 and is in our slide deck in our website to file an NDA next year and to file that NDA we need, these studies to be (inaudible). And that we're doing everything in our power to get the first pharmacologically approved treatment in recent decade for essential tremor patients. So that's how the progress is on.

Yatin Suneja, Guggenheim.

Hey guys, thank you for taking my question, 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.

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 Yatin, 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 won't exist, right? Just a reminder that's 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 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 cohorts enrollment is incredibly fast. So when you have a situation like that, the reduction of potential interim, as we're doing in the final trial, 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, is there -- what is clinically meaningful in terms of mADL, both on 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 on clinical meaningfulness followed the recent, like last year's FDA guidance on patient-driven drug development and on historical guidance in terms of how you anchor these endpoints. Intrinsically, when you anchor the mADL to a known, like disability endpoints, like global impression, what you see is a perfect alignment between chains on the ADL and 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, or 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 the mADL11 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't drink properly from a cup, and now you can, I challenge anyone to tell me that that's not helpful to our patients. It's incredibly meaningful, that's a point or less.

Now, what we are planning to see on this study is obviously more than that. It's quite important as well that the proportion of patients gaining one point, two points, three points, whatever, are prefab. It's not only a point estimation, but also the proportion there. We are monitoring, of course, and we're going to continue to talk about that. If you look into our corporate deck, we talk about achievement of three points. We talk about the 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 likely with significant disability due to their condition.

All right. Maybe one more multiple part, like a classic sell-side question. So, for the interim analysis, this is an efficacy analysis, not utility analysis? Two, 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 points we determine. The data has to be clean transfer 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 communicate at that point in time is what we're going to do. It's a decision that is being held at that point in time with them and so I'll argue the likely decision here is we will update all of you with the results when the full results 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 will be reading out that as well, which we believe will increase. If that is to happen, we will have quite shortly that outcome.

Ritu Baral, TD Cowen.

Good morning, guys. Thanks for taking the question. 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 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, even if -- 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 Phase 2, we had proposed to randomized one of the studies there. The parameters, as you wisely noted there, is the definition, right? Like, we're going to randomize only stables or a stable with another criteria and things like that. And our proposal from the get-go and what's being implemented in the Essential3 was that in the first eight weeks, they would be exposed to a drug with a response criteria, bilateral response criteria, meaning the criteria 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, they 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, “at risk of losing the effects” 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 RADIANT studies, first of all, can we confirm that the RADIANT and POWER1 and POWER2, those are placebo-controlled studies?

Yes. So RADIANT is not placebo-controlled. POWER1 and POWER2 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 RADIANT and POWER2 for 628?

So RADIANT, all patients are going to start at 30 milligrams. POWER1 and POWER2, and we just 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 other six weeks. On POWER2, there is a lower dose as well, just to fulfill potential requirements for a lower dose exposure there.

Here with RADIANT, there are more flexibilities here as well. So maximum [efficacy], which 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 will collect more extensive samples from this, so it becomes a lot easier for us 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.

It was -- I'm glad you bring that up because one of the motivations, actually, for RADIANT includes originally we thought about only conducting focal onsets, 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 that might be, for me at least, is even beyond what we are imagining, the potential of this drug, potential for seizure across the board and things like that, I think we're humbled by it, and about drug development in general.

That is clearly a push. We do expect, by the conversations we had 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 remainder 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 POWER1 and POWER2 of note?

So at this point in time, there are no major differences. 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 [operating] POWER1 is obviously operationally simpler. The second is there is overlapped in terms of sites, expected places we want to go for POWER2, and we wanted to make sure we're underway on the enrollments on POWER1. 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 POWER1. That was the main motivation here.

Understood. Thanks for taking all the questions.

Of course, our pleasure.

Joel Beatty, Baird.

Hi, thanks for taking the questions. 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? 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?

Yeah. Hey, Joel. I'll tackle the second question here first. So, yes, we continuously look into the data in a blinded fashion. 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. So 30 stable patients coming in, as expected, patients doing the study, so all systems are go, green there. That is not the motivation for the planned interim, to do.

On the next update, we do expect to talk about when we have completed all the next stages of the program. So we should see significant updates coming up soon, not only on enrollment, but on the initiation and completion of the interim analysis.

Ami Fadia, Needham.

Hi, good morning. Thanks for taking my questions. Firstly, just a follow-up on 628. What is the gating factor for initiating a physical 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.

Yeah. The motivation here for including generalized, you might recall 628 quite broadly. So this is the first question. 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. We're trying to understand whether or not we can really drive the efficacy of this drug. Now what we're (inaudible) only we're powering double-blind study, but really driving the potential. Maximum here, obviously, that is safety, collection here that would add to the database, that's quite an important.

But maybe even primarily, I keep going back there, but we don't want to, throughout your study, keep collecting more and more PK samples from patients. And I know it sounds minimal, but as we're accelerating towards a potential NDA, that becomes a quite important consideration as well. And as we want to and as we expand the program, right, after POWER1 or POWER2, 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, and particularly our investors, is another milestone here. An intermediate readout before POWER1, we should obviously have more confidence on the overall process, particularly on our end, right? We're working on this program with a very high confidence on the readouts.

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 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 ulixa. Is the interim analysis likely to drive a statistical penalty or not? Thank you.

Yeah, sure. So when you're looking to EMBOLD 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, by Dravet, number one, and then two, by these buckets of unknown things that we call LGS or Lennox-Gastaut most recently, for some instance. But far more patients that have no alternative, there was a reduction as little as it might look or not look, we're obviously not expecting for little reductions here, we're expecting for significant reductions, would significant change, one, their life and their parents' trajectory, but the second is their survival. So we absolutely sure that we're going to be talking during [this], how it extrapolates beyond that.

And that brings me back to our first question about the age, seizure burden there? I think encephalopathies are disease of childhood. 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, and disabilities that are quite prominent. When you see gains there, as we fully expect to see from these patients, that is incredible because their bodies are still developing, their brains are still developing, and there's 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 these 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 grounds.

Douglas Tsao, HC Wainwright.

Hi, good morning. Thanks for taking the questions. 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 six weeks and then moving to 30 milligrams. Why in RADIANT are you going directly to the 30 milligram without sort of a titration period? Thank you.

Yeah. Thanks, Doug. We have a lot of flexibility on RADIANT as we go through the study, we're going to provide periodic updates on how things are going on that study to potentially actually expand as a cohort. So we're not quite there, but your thought about why not just run a generalized epilepsy. Maybe in six months, that's what we're going to be talking about. We're going to be talking about starting that POWER, a 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, as I mentioned before, we want to drive the maximum potential efficacy here, which by definition, the highest concentration. At the same time, we have far more flexibility on RADIANT than we have on POWER1 and POWER2. 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 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. What did they start dose? How do you actually treat patients? After RADIANT, if you see, let's call just for scenario planning, a very significant number are seizure-free. 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 will allow for the best possible decision by the regulators and the physicians. That's how RADIANT plays a role here.

Kambiz Yazdi, Jeffries.

Good morning, team. For PRAX-628, in terms of focal patient enrollment, how will you prioritize it between POWER1 and RADIANT? Then maybe you can go into more details of them, 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 what remains required to advance the program in the US and Europe? Thank you.

Sure. Thanks, Kambiz. So POWER1 and RADIANT are not, I would say, competitive internally or externally. They just go through 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're providing are always slightly different as well. We're trying to actually trip over our goals, I'm going to be perfectly honest, on making sure that 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 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're having outside of the US. We do have some preliminary and should be final soon from Europe as well, which aligns with how we are thinking about this. It will be moving, and that's why we guided for more global parts, including Europe, starting later this year, and in this similar process with the FDA.

We know it's a complex program with 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. I'm showing no further questions in the queue at this time. I will now turn the call back over to Marcio Souza for any closing remarks.

Thanks, everyone. Sincerely appreciate, joining the call and all the questions. We're having quite importantly as well the support for Praxis and all the patients we serve. As you heard at the beginning, we do DARE for MORE, and oftentimes that materialize 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 the Ulixacaltamide hydrochloride, as we will later this year. I hope everyone is as excited as I am about 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 up 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 and 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.

Then without saying on how excited we all are by the number of questions in today's call of 628. 628 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 628. And we're excited on not only getting that to the clinic, potentially in the next two years bringing it to the market revolutionizing the way epilepsy is treated.

So thanks again for the support, look forward to having follow-up calls with you. And we'll see you soon.

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