Praxis Precision Medicines - Q2 2024

Transcript

Operator (participant)

Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Q2 2024 Corporate Update Conference Call. At this time, all participants are on 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 one one 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.

Daniel Ferry (Head of Investor Relations)

Good morning, and welcome to Praxis Precision Medicines Q2 2024 financial results and business update conference call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com. This call is also being recorded. Please note that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking on an obligation to do so.

Please refer to Praxis' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Marcio Souza, President and Chief Executive Officer of Praxis. Tim Kelly, Chief Financial Officer, will also be joining Marcio. After providing updates on our key programs, there will be a brief question-and-answer session. With that, it's my pleasure to turn the call over to Marcio.

Marcio Souza (CEO)

Thank you. Good morning, and welcome to the Praxis Q2 2024 conference call. Praxis is driven by our mission to deliver 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 a registrational phase by 2025. We continue to successfully drive our lead clinical program, ulixacaltamide, towards registration, including the execution of our pivotal Essential3 trials in essential tremor, which expect the top-line 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-its-kind observational study in collaboration with the Epilepsy Study Consortium. We look forward to building on the encouraging preclinical and clinical data generated to date, with top-line results from the first efficacy study expected in the first half of next year. Switching to the upcoming readout this quarter, we remain on track to report top-line results for the phase II EMBOLD studies of relutrigine, or PRAX-562, in pediatric patients with developmental and epileptic encephalopathies. We're very excited about the upcoming readouts and the potential of relutrigine in SCN2A and SCN8A, but also look forward to further 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 medicines for CNS disorders. Let me now spend a few more minutes on ulixacaltamide. 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. Ulixacaltamide is a unique and highly selective small molecule inhibitor of T-type calcium channels designed to block abnormal neuronal burst firing, which should lead, as you've seen, and you're going to be looking into the new study, to improvements of ET symptoms in patients.

It has been only a short nine months since we started the biggest and most comprehensive ET program conducted to date with Essential3, comprised of two simultaneous phase III 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 stratification of key parameters to maintain balance across groups and the implementation of a very comprehensive screening protocol to ensure suitable patients participate in this study. We knew going in Essential3, that the proper endpoint had to be the mADL11, as we 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 probability of success of ulixacaltamide. With all of this in mind, we built in from the very beginning of this study, from the onset, a planned interim analysis for the parallel group study, or study one 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 we're gonna continue to use at this point in time, is that we would read out the study shortly thereafter.

The strong participation we are seeing in Essential3 continues to highlight the significant unmet needs for new therapies in essential tremor, and we really look forward to fulfilling these needs and filing our planned NDA next year. I'll now move to our highly differentiated epilepsy portfolio, beginning with PRAX-628. As a reminder, PRAX-628 is a next-generation functionally selective small molecule from our Cerebrum platform. 628 is currently being developed as a once-daily oral treatment for adults with epilepsy. Building up the strong results seen to 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, a first-in-kind initiative to characterize a very large group of epileptic patients, and among other things, assess the appropriateness of participation in clinical studies. This initiative is conducted under a clinical protocol called EMBOLD, 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 planned 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 engagement and recruitment initiatives are underway, and we plan to enroll up to 50 patients and expect top-line results in the first half of 2025. RADIANT is expected to provide important safety, PK, and efficacy information about 628, and we're really looking forward to it.

POWER-1 and POWER-2 are our 12-week phase III 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-628. With that, I'd now like to turn to our relutrigine program for DEEs, which are a group of severe epilepsies 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 and safe treatments available today.

We look forward to the top-line results from our proof of concept study EMBOLD this quarter. We have been particularly humbled by the severity of the patients in the study and the 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-controlled part of the study, as well as available data from the long-term expansion portion, as appropriate. We believe relutrigine has potential as a best-in-class option, serving as a backbone therapy across multiple DEE indications, and really look forward to discuss that further with you all in the near future. Finally, I'd like to turn to Elanersen or PRAX-222, our ASO designed to selectively decrease expression of SCN2A gene and directly targets the underlying cause of early-onset seizures in SCN2A DEE.

In the Q2 of this year, we initiated the first arm of the global registration study for Elanersen 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 EMBRACE, 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 developments, 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?

Timothy Kelly (CFO)

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 Q2, Praxis spent $27.4 million in operating cash, compared to $20.9 million in the Q1 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 in marketable securities, compared to $81 million of cash in December.

The increase of $352.5 million is primarily due to net proceeds from Praxis January 2024 and April 2024 follow-on public offerings. Our cash supports a runway into 2027 and includes funding all studies that Marcio discussed today to their readout. With that, I will pass it back over to you, Marcio.

Marcio Souza (CEO)

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

Speaker 13

Thank you.

Marcio Souza (CEO)

Operator?

Operator (participant)

Ladies and gentlemen, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Yasmin Rahimi with Piper Sandler. You may start in.

Yasmeen Rahimi (Analyst)

Good morning, team, and congrats on kicking off the energy program. Team, two 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.

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 POWER 1 and POWER 2, given that it has maybe a more broader population, and how you're thinking about enriching that group?

Marcio Souza (CEO)

Absolutely. Morning, Yas. Thanks for the questions. So on the first one, right, if you can, as we look into our slides, like 8 in our corporate deck we posted this morning, you're gonna 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, which is gonna segue to our second question. As we're looking for the study from the get-go, from the very beginning on the prepared remarks, we the possibility of adding an interim analysis, and we did. That was properly discussed and, you know, the very first version 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 for us to do this analysis. Now, in turn, nothing happened along the way. Like, we considered pace of enrollments, type of patient, characteristics of the patient, apply the data. It's all looking exactly as we expected here. So that, that is a check, and that would not be a reason to conduct an interim. But externally, there are factors that, that being, and that might have influenced, like, the way we think.

So when the cost 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 more diligent here, we might have the opportunity to do that. Because we have tremendous interest to the trial, that wouldn't be really a problem for us whatsoever to do that at points, and really continue to the study.

So a big insurance policy on one hand, and not really an indicator that there is anything happening with either the enrollments or the program itself, on the other hand, felt appropriate for us, considering the responsibility 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 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 RADIANT, so RADIANT is a, I think, a phenomenal study to be conducting right now.

It adds an intermediate readout for us, which obviously continue to build excitement of 6-8, to generate data. There are a couple points to generate more. One, again, continue to build the success we're seeing now with patients that have uncontrolled seizures, both with focal seizures and generalized. But the second is we want to, and we believe that since we're accelerating pretty quickly to a potential NDA, not too 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, and conducting that in an ongoing study, that is what is operationally far easier, is the second parameter.

And, is our first foray on patients with generalized, where we're gonna get, like, an even potential for a second indication here in the future. So understanding that as well. All of that on 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, this way it's gonna be. So, it was a no-brainer. Of course, we're gonna learn things as well on this study that is gonna help our package. So when you look into a potential package for registration here, POWER 1, POWER 2, and whatever we learned from safety and exposure relationships and so on, and RADIANT should be that package in the near future.

Sorry for the long answer there, and hopefully, I answered everything you asked.

Yasmeen Rahimi (Analyst)

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

Marcio Souza (CEO)

Thanks, guys.

Operator (participant)

Thank you. Our next question coming from the line of Joon Lee with Truist. Your line is open.

Joon Lee (Analyst)

Hey, yeah, congrats on the progress, and thanks for taking our questions. 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, that 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 is an interim for study two, I believe. I have a follow-up question. Thank you.

Marcio Souza (CEO)

Yeah. So, thanks so much, Joon. So study one and study two now are, is slotted to run, to read out together, right, as you know. We're still expecting to be the case, as we do expect, as you properly were there, the interim is just gonna 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 one, then they would be separated. We don't believe by a very large period of time, because we do have sufficient patients. We're not gonna be closing the screening and pre-randomization work for the study one. It will be quite fast, if that happened.

Was one of the motivations, to be honest, on our end, so we have, like, enough patients that wouldn't be a delay and creates like, a significant cohort effect.

Joon Lee (Analyst)

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, help us set some bar for what you think is a good data and what you, you know, from SCN2A and SCN8A. And are you saying that, you know, the, the opportunity in SCN2A and SCN8A 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.

Marcio Souza (CEO)

Yeah, no, that's and thanks for that. So we continue to monitor the progress here. We are really very, very close to that readout, right? Incredibly excited. But there are two things there that I mentioned on the prepared remarks. Just gonna 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 to actually drive some relief for themselves, for their families, which is exciting for us. We guided before, we're gonna continue to guide at this point in 20%-30% seizure reduction. We think that would be quite phenomenal, from the sample size we have, from the type of patients in the trial. Of course, we want to see patients doing as well as possible.

You might have caught as well, the fact that you're gonna have a, in my view, a significant number of patients crossing the, long-term extension. So we're gonna be able to talk about what happens when they continue taking the drug, and so on. So that is the there. Then when you open, I would say, the horizon here and to other DEEs, 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 Steven Petrou and David Goldstein and others, started, like, looking into this in detail, and Sam and other folks. But the use of, very toxic, but it's still efficacious, sodium channel modulators, is pretty wide.

So if you take nothing else but this, 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 DE that anyone ever talked about. As we look into that, what you're probably gonna be hearing from us, it's a broader approach in terms of, like, patients who have very severe uncontrolled and pediatric IG, because that is the key here, right? So very different manifestations. They get older, probably not as severe as it is when they are young. That number is pretty big, not only from a market opportunity, but from a unmet needs opportunity, and I think that that's focusing on right now.

Joon Lee (Analyst)

Taking a question.

Marcio Souza (CEO)

Thank you.

Operator (participant)

Thank you. Our next question coming from the line of François Brisebois with Oppenheimer. Your line is open.

François Brisebois (Analyst)

Hi, thanks for taking the question. So just first of all, so you mentioned that 20%-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.

Marcio Souza (CEO)

Yeah. So thanks for the question. So we are like, again, we keep guiding here, and we're going to continue to for 20%-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 seizures in some of those patients. There are things that are incredibly uncommon, like significant reduction, potential seizure-free periods, like without seizure and things like that. So we're kind of weeks away, I would say, since we guided for Q3, so I'm gonna 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 unknown for having very poor tolerability with any agents they take. And, and I can say, because tolerability is not blinded, right, we're after all the study, that is not the case. We're seeing very good tolerability with, 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, it's in our footstep, it's very close for us to, to be talking about this, so we're gonna be having a full song discussion as the results are out.

François Brisebois (Analyst)

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 and the thought process between doing parallel and randomized withdrawal, and just overall, just maybe going through the differences that make you feel comfortable with the readout or more comfortable than what others ran into here? Thank you.

Marcio Souza (CEO)

Yeah. So the thoughts from the get-go on the, I always start with the randomized withdrawal here, because I think it's quite interesting, right? The way drugs are used in the markets is a patient takes drug, and if they respond, they stay on the drug, responds, they discontinue. And I know it sounds insanely odd, what I just said, but it doesn't feel like when we have patients like this, on how obvious it is. Then you go back to how it tests 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, internally, that was quite important to establish, like, what happened with these patients.

Maybe remind everyone that patients with essential tremor tolerate anything. They are giving, like, a lot of other potential therapies, and they continue all of them. Like, the retention rate is like 60% retention on treatment. So that was quite important. Now, that study is pretty straightforward in a sense that we sized that significantly higher than we believe we need, so that's why we're continuing that. 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, as being many, many discussions in the field essential tremor never had a pharmacological treatment approved.

We did a very comprehensive study and analysis of Essential1, if we understand the groups really well, and we powered the 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, and continues to be important, to understand how this heterogeneous group of patients, since there is not a one determinant of essential tremor, behave when you expose them to a relatively long period of time, like 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 and all the indicators as we're expecting. But we still have that unknown of heterogeneous population that might influence things as likely one way or another. That's why we're planning, that we are planning right now.

This is a registrational package, and we want to make sure, as you heard in our disclosures, and it is in our slide deck, in our website, to file an NDA next year. And to file that NDA, we need a study to be positive, 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 progress is designed.

Operator (participant)

Thank you. Our next question coming from the line of Yatin Suneja with Guggenheim.

Yatin Suneja (Analyst)

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 will be the sample size that will trigger it? So that's one. What exactly are you looking for? Is there a particular mADL11 delta you're shooting for there? And then is there an alpha loss there since you do an interim analysis, and what sort of an alpha loss? And then I have a follow-up on the other program.

Marcio Souza (CEO)

So the interim is based, and while I'm not gonna give you the information points here, you have to, and I'm sure you do, and 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 reestimation, one exists, right? It's just a reminder that not our base assumption. The base assumption is situation without reestimation. Reestimation happens, it's gonna 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 like final cohort enrollment is incredibly fast. So when you have a situation like that, the readout potential interim, as we're doing, and the final are pretty close together. So we are considering that, as well, as we're completing this study.

Yatin Suneja (Analyst)

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

Marcio Souza (CEO)

Yeah. When you look back, most of the work, if not all of the work, that for clinical meaningfulness, follow the recent, like, last year's FDA guidance on patient-driven drug plans and 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 changes on the ADL, changes 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, well, talk to physicians, and you ask them what they 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 mADL 11, as is required, on this study, that is obviously dropped below 1 point. This study is well powered beyond that, but that would be the logical and proper answer is, if we can think properly from a patient's, and now you can, I challenge anyone to tell me that that's not to our patients. It's incredibly meaningful. That's a point or less, right? Now, what we are planning to see, on this study is obviously more than that. But it's quite important as well that the proportion of patients gaining 1 points, 2 points, 3 points, whatever, are of interest. 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 movement of three points. We talk about, like, proportion of patients that are there and so on. So it's very clear that this is gonna be a quite meaningful treatment for patients with Essential Tremor, especially the ones that are, like, with significant disability due to their conditions.

Yatin Suneja (Analyst)

All right, maybe one more multiple part, like a classic sell-side question. So for the interim analysis, this is an efficacy analysis, not fut 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.

Marcio Souza (CEO)

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, transferred to an external independent data monitoring committee, and then the analysis should be to— So, and coming back to us and so on. A little while, that's why, therefore, the timeline. The, what we intend to communicate point in time, is what we're gonna do, is the decision that is being held at that point in time, with the analysis. So the... I'll argue the likely decision here is we would update all of you with the readout, when the full readout for this study is gonna happen.

And in the eventuality that we believe is appropriate, as recommended by the IDMC, to increase the samples, what is the increase, and we would be reading out that as well, which we believe available increase. If that is to happen, we would have quietly quite shortly there are.

Operator (participant)

Thank you. And our next question coming from the line of Ritu Baral with TD Cowen. Your line is open.

Ritu Baral (Analyst)

Good morning, guys. Thanks for taking the question. I have got one last question on ulixacaltamide and then a bunch on 628. So for the essential, the withdrawal study, I know that sometimes FDA imposes a official or unofficial requirement on the initial response rate for those patients going in that are defined as responders before the actual withdrawal portion, is conducted, and analyzed. Have you spoken to FDA around the design of the withdrawal study, specifically on that initial open label responder rate, sort of what they're looking for, even if and if there is even a hard requirement or just a soft would like to have?

Marcio Souza (CEO)

Yeah, no, thanks, Ritu. From the beginning as well, even actually from the phase II, we had proposed the randomized as one of the studies there, right? Parameters, as you wisely noted, there is a definition, right? Like, we're gonna randomize only stables or a stable with another criterion, things like that. In our proposal from the get-go, and what's being implemented in Essential3, was that in the first eight weeks, they would be exposed to drug with a response criteria, bilateral response criteria, meaning the criteria increase and decrease is identical. If they cross that boundary, we're gonna 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 and 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 study remains blinded for the entire duration of the trial. 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.

Ritu Baral (Analyst)

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

Marcio Souza (CEO)

They are all randomized under the same conditions.

Ritu Baral (Analyst)

They're all blinded already. Okay.

Marcio Souza (CEO)

Yes. Correct.

Ritu Baral (Analyst)

Okay.

Marcio Souza (CEO)

Yes.

Ritu Baral (Analyst)

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

Marcio Souza (CEO)

Yeah. So RADIANT is not placebo-controlled. POWER 1 and POWER 2 are placebo-controlled.

Ritu Baral (Analyst)

Got it. And then what doses are you using? Just given the you know, very good safety that you've seen, what doses are you using in RADIANT and POWER 2 for 628?

Marcio Souza (CEO)

Yeah. So RADIANT, all patients are gonna start at 30 milligrams. POWER 1 and 2, and we updated the schematics in our PowerPoint on our website as well. Patients will start at 20 milligrams for 6 weeks, and then 30 milligrams for the 4 other 6 weeks. On POWER 2, there is a lower dose as well, just to fulfill potential requirements for a lower dosage exposure there. The deal with RADIANT, there are more flexibilities here as well. So our max dose, which will be derived from day one, but it's here 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 drug or which dose they are in, because that could interfere.

So that, 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.

Ritu Baral (Analyst)

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 Doug checks, our, some of our KOLs were particularly excited about the potential for 628 in this population.

Marcio Souza (CEO)

It was, I'm glad you bring that up, because one of the motivations actually for including originally, we thought about only conducting focal 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 board, I think what they are imagining, and that might be it for me at least, is even beyond what we are imagining, potential of this drug, potential for seizure across 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 gonna be enrolling and the investigators in general, they're gonna 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.

Ritu Baral (Analyst)

Got it. Got it. Then final question. Thanks for your patience. Other than the dosing, do you see, in the design, are there any major differences between POWER 1 and POWER 2 of note?

Marcio Souza (CEO)

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

Ritu Baral (Analyst)

Understood. Thanks for taking all the questions.

Marcio Souza (CEO)

Of course. Our pleasure.

Operator (participant)

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

Joel Beatty (Analyst)

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?

Marcio Souza (CEO)

Yeah. Hey, Joel. So I'll tackle the second question here first. So yes, we continuously look into the data in a blinded fashion, and I 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, is actually as expected, lower beforehand. So fairly stable patients coming in, as expected, patients during the study. So all systems are go, are green there. That is not the motivation for the plans interim to do. On the next updates, we do to talk about when we have completed all the next stages, program.

Also, you should see updates coming up soon on not only enrollments, but on the initiation and completion of the interim analysis.

Joel Beatty (Analyst)

Great. Thank you.

Operator (participant)

Thank you. Our next question coming from the line of Ami Fadia with Needham. Your line is open.

Ami Fadia (Analyst)

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-up.

Marcio Souza (CEO)

Yeah. The motivation here for including generalized, you might recall, 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 RADIANT is to understand whether or not we can really drive the efficacy of this drug. Not what when we're powering, double blind study, but really driving, the potential maximum here. Obviously, there is 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 our study, keep like collecting more and more PK samples from patients. And I, I know it sounds minimal, but as we're gearing towards a potential NDA, that becomes a quite important consideration as well. And as we want to expand the program, right, after POWER 2, very, very likely adding 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, in particularly, our investors, is another milestone here and an intermediate like readouts before POWER 1, which should obviously more confidence on, on the overall product, particularly on our end, right?

We're on this program with a very high confidence on the readouts.

Ami Fadia (Analyst)

Got it. That's quite helpful. With regards to PRAX-562, can you talk about how age and baseline severity impact how much seizure reduction we could expect to see? Also, how 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 Elanersen. Is the interim analysis likely to drive a statistical penalty or not? Thank you.

Marcio Souza (CEO)

Yeah, sure. So we're looking involved in the upcoming results. I think we absolutely should look into this and how it extrapolates to other DEEs. The world of DEE is being dominated by this, by DRVN, number one, and then two, by these buckets of unknown things that we call GS or idiopathic, most recently, some instance. But there are far more patients that have no alternative, that would 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're absolutely sure that we're gonna be talking during extrapolate, beyond that.

Back to your first questions about the age, seizure burden there. Developmental encephalopathies are, encephalopathies are disease of childhood, right? When you look into the patients that enrolled in our study, as you're gonna 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 incredibly meaningful because their bodies are still developing, their brains are 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 DEEs, that don't really have any opportunity.

They have similar characteristics, young, high seizure burden, very low ability to treat, mostly because of safety and tolerability throughout.

Operator (participant)

Thank you. Our next question coming from the line of Douglas Tsao with H.C. Wainwright. Your line is open.

Douglas Tsao (Analyst)

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 six two eight'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, you're starting at 20 milligrams for 6 weeks and then moving to 30. Why in RADIANT are you going directly to the 30 without sort of a titration period? Thank you.

Marcio Souza (CEO)

Yeah. Thanks, Doc. So we have a lot of flexibility on RADIANT to, as we go through this study, we're gonna provide periodic updates on how things are going on that study to potentially actually expand the cohorts. 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 gonna be talking about. We're gonna be talking about starting that trial, that controlled study in generalized. I think first we wanted to understand the impact we could have, which we believe is gonna be fairly large in both focal and generalized epilepsy. The second question on the dose, I mentioned before, we want to drive the maximal potential efficacy here, with the definition the highest concentration.

At the same time, we have far flexibility on RADIANT than we have on POWER 1. We do need to have some, like 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 obviously sufficient. And that is gonna be a quite important discussion decision with regulators once that is significant, and then the 30. So what did they start doing? How do you activate with patients? But after RADIANT, if you see, let's call just scenario planning, a very significant number 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's gonna allow for the best possible decision by the regulators and the physicians, and that's how RADIANT plays a role here.

Operator (participant)

Thank you. Our next question coming from the line of Kambiz Yazdi with Jefferies. Your line is open.

Kambiz Yazdi (Analyst)

Morning, team. For PRAX-628, in terms of focal patient enrollment, how will you prioritize it between POWER 1 and RADIANT? Then, maybe you can go into more details of the EMBOLD observational study. Then, for another program, Elanersen, 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 US and Europe? Thank you.

Marcio Souza (CEO)

Sure. Thanks, thanks, Kambiz. So POWER 1 and RADIANT are not, I would say, competitive internally from a first or external. They just goes through, it's a much larger initiative, as you can imagine, POWER 1. So all the administrative stuff that has to happen takes a little bit longer. It's a smaller number of sites for Radiant, so that's part of that as well. And the patient characteristics we might enroll is slightly different as well. So we were trying to actually trip over our, I'm gonna be perfectly honest, on making that both studies recruits quite excellently, as we expect to. So we—again, no, no competitiveness there whatsoever.

I think your second question about the nursing, we do, we do have obviously a full feedback from Brazil, and we're able to start the study there. I believe that cohort is gonna be quite complementary to the initiatives that we're having outside of the U.S. We do have some preliminary and should be final soon from Europe as well, which are aligned with how we are thinking about them be moving, and that's why we guided for more global parts, including Europe part of starting later this year, and in the similar process with the FDA. We know it's a complex program with, like, multiple variables here. The most important of them is just how severe those patients are.

We're taking one step at a time on that program.

Operator (participant)

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.

Marcio Souza (CEO)

Thanks, everyone. Sincerely appreciate it, 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 deliver more, and oftentimes they materialize on actually looking ourselves in the mirror and seeing what is best for the patients we serve. In the case of this call, it's really delivering successful studies for patients with essential tremor, with ulixacaltamide hydrochloride, as we will later this year. I hope everyone is as excited as I am about the upcoming results.

And just a reminder, in a few short weeks, before the end of the quarter, we're gonna be talking about our results for our previous 562, relutrigine, now as we're calling, which brings a quite important upside for all of us in terms of from an investor perspective. But most importantly, SCN2A, SCN8A, have no treatments either available, approved, or in development, 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 is quite exciting. And then, without saying on how excited we all are by the number of questions in today's call with 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 few years, bringing market and revolutionizing the way epilepsy is treated. So again, for the support, look forward to having follow-up calls with you, and we'll see you soon.

Operator (participant)

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