PRAX - NASDAQ

Good day and thank you for standing by. Welcome to the Praxis Precision Medicines Third Quarter 2024 Corporate Update. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions]. I would now like to hand the conference over to your speaker today, Dan Ferry from LifeSci.

Good morning, and welcome to Praxis Precision Medicines third 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. 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. Joining the call today are Marcio Souza, President and Chief Executive Officer of Praxis; and Tim Kelly, Chief Financial Officer. 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 third quarter 2024 conference call. This past quarter, we remain laser-focused on advancing our pipeline as we gear up for next year to have four programs in registration totaling to a substantial multibillion dollar opportunity. The Phase 3 study in Essential Tremor Essential3 for our lead program ulixacaltamide continues to progress well. We have confirmed all aspects of the interim analysis and are now updating the plans to have the results in Q1 2025. Both studies are well-powered and controlled for success because there's a range of outcomes for each study as well as the interim analysis in the coming months. We decided that we will only share an update on timing for both Study 1 and Study 2 once we have evaluated the recommendation from the interim review board for the interim analysis. In Q3, we're very excited to report the positive top-line results for another asset in our pipeline, relutrigine in the Phase 2 EMBOLD trial in SCN2A and SCN8A-DEEs. In the 15 patient study, relutrigine demonstrated an impressive 46% reduction in motor seizures versus placebo, with one-third of the patients achieving an unprecedented seizure free status. Based on those results, we initiated a second registrational cohorts of the EMBOLD study, which has already started screening patients just weeks after completion of the prior cohorts. In common epilepsies, vormatrigine, previously known as PRAX-628 is starting out of the gate strong in all areas of our comprehensive ENERGY clinical program. The innovative observational study EMPOWER, a first of its kind in collaboration with the Epilepsy Study Consortium, launched in the third quarter, and in this short period of time attracted the interest of over 1,000 patients who registered in the study. We expect the key learnings from EMPOWER to impact the entire Energy program. The Phase 2 RADIANT and the Phase 2/3 POWER1 trials are on track for top-line results next year. Rounding out our portfolio, Elsunersen begin dosing patients in Brazil in the second quarter for the EMBRAVE study and we continue to engage with regulatory agencies in Europe and in the U.S. to finalize the development plans in SCN2A gain of function patients. With our strong balance sheet, we continue to be fully funded as we pursue our vision to deliver precision therapies for patients with CNS disorders. Let me now focus some more on ulixa. Our innovative Essential3 program in ET is the biggest and most comprehensive program conducted today. We began recruiting for the two Phase 3 studies just about one year ago and have seen tens of thousands of patients interested in participating. This vibrant participation highlights the significant unmet need for the millions of patients with Essential Tremor in their physicians and caregivers who are seeking a therapy that will allow patients to perform daily activities without impairments. The needs for treatments in Essential Tremor continues to be more defined as we advance this program. In a survey we conducted with over 400 patients, up to 77% of the respondents said they do not feel their ET symptoms are managed with current treatments. In a separate survey, we conducted with 150 treating physicians, they shared that 85% of their visits with ET patients are focused on looking for treatments. Clearly, there is an incredible need here and we look forward to shortly completing the Essential3 study with the goal of bringing an option to the market. As a quick refresher, the Essential3 program has two simultaneous Phase 3 studies being run concurrently. Study 1 is a 12-week two-arm placebo-controlled Parallel Group Study and Study 2 is a 12-week Randomized Withdrawal Study. Both studies use as primary assessments the change in the modified activity of daily living and they're both run entirely decentralized as in the patient's home rather than at a clinical sites. We shared on our last quarterly call that we decided to trigger a pre-planned interim analysis when 50% to 75% of the patients have completed the 12-week Study 1. The analysis will inform us whether we should continue the study throughout completion if the primary endpoint is met to consider seizing the study or to consider enrolling additional patients to ensure it's sufficiently powered for success. Based on the expectation for the sufficient number of patients to complete stage study cleaning of the data, execution of the statistical testing and analysis by an independent boards and our internal operations, as well as considering the operational impact in the study completion of Study 2 will be finalizing the interim analysis in the first quarter of 2025. Given the range of outcomes, we will not speculate on scenarios or timing for results of Study 1 and Study 2 until we hear from the internal review boards, at which time we'll be better informed to provide an update. Regardless, preparations continue to file the NDA as expected in 2025. Now moving on to our highly differentiated epilepsy portfolio. Vormatrigine previously known as PRAX-628 is a next-generation functionally selective small molecule being developed as a once-daily oral treatment for adults with epilepsy. We know that treatment options for common epilepsies are lacking in both efficacy and tolerability and we believe the profile emerging with vormatrigine will provide a highly differentiated paradigm shifting way to treat this disease. Last quarter, we introduced our broad ENERGY clinical program for vormatrigine in focal and generalized epilepsy and I'm glad to share that the ambitious multi-study goals we aim to achieve are advancing well. 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 vormatrigine. Three trials of ENERGY are to evaluate the efficacy and safety. The first of this is RADIANT, an open-label study that will enroll patients with either focal or generalized epilepsy who will receive vormatrigine for eight weeks with update follow-up of two weeks. We are on track to deliver on top-line results in the first half of 2025, which should help us better understand the effectiveness levels of vormatrigine and its pharmacology in the patient population. The POWER1 and POWER2 studies are 12-week Phase 2/3 studies in patients with focal onset seizures. POWER1 is underway and we anticipate top-line results towards the end of 2025. We will slightly stagger the initiation of POWER2 to begin recruiting in the first half of 2025. The combined studies are expected to enroll approximately 500 patients globally. As we consider other areas where vormatrigine can play an important role, it's clear that its activities in Nav 1.7 and Nav 1.8 coupled with fast-acting pharmacology and safety profile could play an important role in pain management. We are concluding our assessments about the potential role of vormatrigine in pain and will be sharing more in the near future. Now turning to our relutrigine, a functioning state modulator that is formulated for pediatric use in DEEs, a group of severe epilepsies characterized by developmental delays with early onset. With SCN2A and SCN8A being one of the most severe and refractory forms of these and where currently there is no approved treatment. As a reminder, relutrigine has orphan and rare pediatric designation for these two indications. We are thrilled and humbled to share the unparalleled results we observed in Phase 2 EMBOLD trial Cohort 1 in SCN2A and 8A last quarter where relutrigine demonstrated a number of impressive and unprecedented data points. This two-arm study was run over 16 weeks with four, four-week periods. Patients in the placebo arm were administered placebo for one periods and relutrigine for the other three periods and neither the patient or investigators were aware, which period was on placebo. 15 patients completed a study and patients had the option to continue to an open-label extension after the 16 weeks. A robust 46% placebo adjusted reduction in motor seizures over the period was observed with 33% or 5 out of 15 patients achieving seizure free status that notably was never seen before in the severe patient population. In addition, we saw disease modifying impact noted in the study by both caregivers and clinicians with relutrigine leading to meaningful improvements in overall wellbeing of patients in areas of seizure severity, intensity, alertness, and other important measures. This is also very impressive, an encouraging finding given not only the severity of the disease but also the lack of improvements in these areas with currently available treatments. Lastly, relutrigine was generally well tolerated with no drug-related series adverse events or dose reductions required during the study. These results further set up relutrigine as the potential first and best-in-class treatments and following the successful proof of concept, we initiated screening for Cohort 2 update study, which aims to enroll 80 patients and has been receiving interest from physicians and caregivers, moving us closer to our goal of bringing a potential precision therapy for those severe patients. In addition, across all these, which affected nearly 200,000 people in the U.S., 70% to 80% of the patients are currently on a sodium channel block. When we see the data from relutrigine, which use a more target approach on the sodium channel mechanism of action, we believe there is a broader potential for relutrigine across all DEEs. With that in mind, we are already diligently working with the regulatory agencies to finalize the EMERALD study protocol for all DEEs. We expect to finalize by the end of this quarter and initiate in 2025. We're very excited by both the potential and the progress of our sodium channel modulators vormatrigine and relutrigine and there's a lot more to come in 2025. Rounding out our clinical epilepsy program is our first ASO Elsunersen, designed to selectively decrease expression of the SCN2A gene and directly target the underlying cause in early onset seizures in SCN2A-DEE. Last quarter, we continued Part A of the EMBRAVE protocol in Brazil. This part of the study will provide important control data examine the safety and effectiveness of Elsunersen in a very severe disease population. This continues to be an exciting time for Praxis and 2024 has been a transformative year. Looking ahead to 2025, we have a number of inflection points and we remain the rigorous focus on execution. We look forward to our potential first of many NDA submissions in 2025. With that in mind, let me now turn the call over to our Chief Financial Officer, Tim Kelly. Tim?

Thanks, Marcio, and good morning, everybody, and thank you for joining today's call. I'll provide a quick summary on our third quarter financials. In Q3, our operating expenses were $57.1 million, with $41.9 million of that for R&D, and the remaining $15.3 million for G&A and reflects an increased amount of clinical activity in our movement disorder and epilepsy programs. During the third quarter, Praxis spent $27.7 million in operating cash, similar to the second quarter of 2024, and it reflects our focus on working capital. We ended Q3 with $411.2 million in cash, cash equivalents and marketable securities, which compares to $81.3 million of cash at December 31, 2023, with the increase primarily due to the net proceeds from Praxis follow-on public offerings earlier this year. Our cash supports the runway into 2027 and it includes funding all of the programs that Marcio discussed today through their readouts. Now, I'll pass it over to you, Marcio.

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

Thank you. [Operator Instructions]. Our first question comes from Ritu Baral with TD Cowen. You may proceed.

Good morning, guys. Thanks for taking the question. A couple questions on relutrigine Praxis to for DEE. Specifically, as you think about the 80 patients in the expanded cohort for 80 patients, expanded cohort sufficient for registration, will the enrollment criteria for that 80 patients be any different than the original 15 patients? And if so, do you expect it to result in any or prospectively expected to result in any changes to efficacy or safety? And then, the second part of that question is, you mentioned that you are seeking alignment with regulators in the first half. Can you talk to maybe any more specifics around that timing? How you might expect Cohort 2 to change based on feedback? And any specifics on what you're asking on EMERALD? Thanks.

Sounds good. Thanks, Ritu for the question. So on the first one for the 80 additional patients that are enrolling on the second cohort on the study right now, so number one, like there are active patients. So we've been eye screening those patients and getting them into the study, which is very good news in our view. The major difference I would call on this study is actually the start dose for the patients randomized to drug. So starting on the previous study was at 0.5 mg/kg per day and this one is 1 mg/kg per day. So straight up into the one we believe to be the most efficacious. So we believe the impact is going to be on that. It's just a fast or faster, may I say effect in terms of like separation and a deeper effect possibly maintaining or even expanding the number of seizure free days and number of patients there. No real major like change on the inclusion criteria. So from a patient population perspective, we're not expecting to see a different one here. And then on the timing for EMERALD, so we do have a protocol. We are aligning on specifics there. I would say, it's a little bit more maybe traditional as what I would call we're expecting to run like a Parallel Group 1 to 1 12 weeks. What we are aligning is really the inclusion of those patients. So our view and our position right now is that we can phenotypically define patients with DEE independently of their genotypical like etiology. And for as long as they have non-sensitive mechanism number one and two seizure burden that are consistent with what we believe we can play a high impact, that should be sufficient. So just double checking, there's like a number of like small details in terms of how to randomize and size and things like that, which should be done by the very end of the year and then we're going to be able to operationalize by the very beginning of next year.

Got it. So I want to clarify, you are going to genotype these patients but all they need to have is a genetic mechanism that's rational for --

That is right.

Okay. Got it. Thank you.

You're welcome. Thank you.

Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. You may proceed.

Good morning, team. Thank you so much for all the thoughtful comments. Few questions on the interim analysis. I think investors were just wondering, I think the interim was expected to happen end of year, maybe just some color around why it got a little bit moved into 1Q 2025. And then it appears based on the remarks you've made that we're Study 2 will not readout before the interim or at the interim, we'll get an insight about 1 and 2. I just want to make sure, just to get if you could just walk us through sort of the disclosures around both of the studies that, that could be helpful. Then last question is, I think you guys noted that upon the outcome of the data in ET, you would reinitiate a Parkinson's disease program in 2025. Could you maybe comment on like the success an ET would move you into Parkinson's or would that be a Phase 2 study, Phase 3 study? Any color around that would be helpful and I'll jump back into the queue.

Sounds good, Yas, and thanks, Yas. So starting on the interim, right, so I'll start by saying we're very confident on the execution for the interim. Like every aspect that our monitoring and every discussion just increase our confidence on a successful like execution. Of course, it is biased towards our success to begin with and making sure we wrap up the program like concomitantly to slash shortly thereafter to the entrance and that was the -- I would say the main driver here, right? So what we're trying to do to take a step back is to deliver a successful program that we can file an NDA and can be incredibly clear the efficacy, the safety of ulixacaltamide hydrochloride for these patients. When you look into that, there is -- there was a number of things that were either bumping up in terms of availability of top identity [ph] members, their ability to conduct the analysis, cleaning up the data. And I would argue the most important factor here is the influence on Study 2. That is the second part of your question. In the eventuality, which is quite possibility that the interim analysis work exactly as we expect, so very positive. We wanted to make sure the result of Study 2 is about the same time too shortly thereafter, number one. But two, that there is no influence and by influence I mean negative influence on Study 2 readouts. So when you're looking into as a program it made sense for us to make this, which in our view is a small and slight chain that is safeguarding the overall like positive results in our view of the combined studies, right, Study 1, Study 2, its combination and the package for the NDA. So that is the main rationale on our end. Everything is progressing brilliantly so far. On the Parkinson's disease study, I think that as our confidence grows into the outcome on Essential Tremor, we need to really be ready to the expansion like time is an incredibly important asset on this business. We want to make sure that the an indication of value for ourselves, for potential strategics and so on, so forth gets off the grounds. We had got some feedback from the FDA last time in terms of what they would like to see on a PD study. So we have a very good idea to design a Phase 2/3 study in Parkinson's that would significantly advance this program as well. So we're just restarting that in terms of the planning. So we are ready at that time to kick off and restart. So we have a portfolio of indications and correlates instead of just one.

Great. Thank you. And I'll jump back in the queue.

Sounds good.

Thank you. Our next question comes from Joon Lee with Truist Securities. You may proceed.

Hey, thanks for the updates guys. Just a quick clarification. Will you be including Lennox-Gastaut in the broader DEE study? Because there's no genetic basis for Lennox-Gastaut and you seem to want to stick to genetic epilepsy based on your response to Ritu's question. And I have a follow-up.

Sounds good. Joon, we will include LGS patients on this who attempt to the answer again to Ritu before, we are providing an attempt to collect as much genotype information, sometimes as you know they're going to be phenotypically defined, clinically defined, and not have like a final diagnosed there. But we believe that as these patients are right now, when you're looking to actually data on the literature on claims data for LGS, it's one of the highest use of the actual sodium channel mechanism with one of the highest issues in terms of tolerability, which we think is a sweet spot for our drugs. So yes, we will be doing. But at the same time, that is part of this entire discussion about inclusion criteria and measuring is the discussion we're having right now.

Great. So it's a two DEE study. Great. For the interim analysis for Essential programs. Just wanted to clarify that you're -- when you refer to interim analysis, you're referring to the Study 1 interim. So your Randomized Withdrawal trial top-line will depend on the interim from the parallel comparator trial, is that correct? And then is --

Yes.

Yes.

Go ahead, Joon. I'm sorry.

Yes. So -- and then number part two is that, is there or is there no inferiority analysis baked into that interim analysis?

Yes. So the interim analysis is on Study 1 only as you mentioned, right? We don't believe that would be necessary or appropriate for an interim on Study 2. The -- basically there's an alignment in terms of like database log claiming between the multiple events that we're talking here. So that it could be somewhat of an influence because those studies are recruited concomitantly as you know, from the same pool of patients and they are randomized to their studies. So that's why there could be some influence depending on the outcome of the interim analysis as well. We will be reading out Study 2 of course shortly thereafter on the end trend that is easier one could argue study to monitor based on like event rates and things like that, so quite bullish about that to begin with. What was the second part of your question about the inferiority? Sorry. So that is a fertility margin on the lower end of the conditional power as it standards, right, on interims like that. So fairly standard in terms of the bottom there, a fairly wise I would say sample size re-estimation zone because that's why -- the reason why they study or the interim analysis was designed to begin with and on the other end as well, which should be considered that is a stop for overwhelming efficacy as well. You were wanted to balance all of that of course from an information fraction perspective and from spending perspective and the overall execution to drive towards a successful outcome.

Great. And then last question, as we look to the very likely approval of Relutrigine in January, it's actually impressive that it even works at all because it only targets one of the three voltage-gated sodium channels in the peripheral nervous system. So it's actually interesting that you're advanced, looking at your formulating in pain as well, which targets two out of the three pain receptors or not receptors, but voltage-gated channels. Any anecdotal evidence of pain reduction from your Phase 1 or any other studies. Thank you.

Yes. So the like we're super excited about this as well. We've been looking to for a while. It's not something that made sense from priority execution, capital allocation beforehand for us, but now we believe it does. We do have a very strong preclinical evidence on in pain models and in general like very potent inhibitor of 1.7 and 1.8. As you know, that mechanism and the duality of the mechanism is quite important in pain generally acute and sub-chronic and chronic pain. We thought that -- yes, we are excited with what we're seeing and we think that what's most appropriate for us is just to finalize everything, look into from a competitive standpoint as well, make sure that we'd be competitive and then talk about our plan early in the year with all of you.

Thanks for all your answers.

Of course. Thank you.

Thank you. Our next question comes from Francois Brisebois with Oppenheimer. You may proceed.

Hi, thanks for the questions, and thanks for kind of going through the potential scenarios here and the complexity and the dependence between or the impact of Study 1 on Study 2. But in terms of what to share on the interim, could it go into data or that's actually a really good case scenario where we stop the study because things are working out or is it more -- can we be assured that the actual top-line of Study 1 will be after Study 2? That might come short after the interim look, just any help there, understanding the timeline of the top-line versus the interim for Study 1.

Yes, Francois, thank you. So the like I think the scenarios like if I think about bookends here, so one, as you mentioned, like the potential to stop like for overall efficacy that obviously is not the base case. Let's just play that out. And then both studies would be having the results at the same time, right, like Study 1 and Study 2 at that point in time, which obviously would be a quite positive complete package and so on. I think that is now an opportunity as well to increase the size of Study 1. And on that case, the conversation will be having as we're moving Study 1 forward, we're increasing the size. And for Study 2, we should have the results very quickly as well. So that's when it dissociates the two. That is the highest a priority probability that would happen is on that just because the range of the conditional power is the largest or the widest on that zone. So I think that the two. I would say, we should plan the most around with the first one having the highest impact, right, in terms of like operationally making sure ready to like wrapping up the other two studies and so on. So that's what we one of the considerations and how it looks into being ready for the interim.

Okay. Thank you. And then on the DEE commercial front, there's a lot of different ways to look at this market. Can you help us understand U.S., ex-U.S., how you think about the commercial potential here?

Yes. The vast majority of the business, and I would say from a dollar value perspective is in the United States, our modeling shows around 70% in the U.S. and then the about 30% outside of the U.S. for a pick. We're talking about a multibillion dollar pick here in DEEs, right? We just completed yet like another refinement of the epidemiology in the U.S. and looking into the utilization of the mechanism limitations and so on. And it's a little bit shy of 200,000 patients in the U.S., when you consider that even relatively small market share gets to quite important figures in terms of like the potential pick revenue. And then the outside of the U.S. becomes a little bit more. I'm going to call opportunistic from a business perspective, obviously important to have access to patients as well, but not as important to get the drug off the ground and get quite meaningful revenue. So about two-thirds in the U.S., one-third outside of the U.S. that's how we've been modeling.

Thank you.

Thank you.

Thank you. Our next question comes from Yatin Suneja with Guggenheim. You may proceed.

Hey guys, thank you for taking my question. Just a couple for me as well mostly on the ET side. Could you provide us where you are at least on the enrollment front, like how many patients have been enrolled in Study 1 and 2, if you could? And then we understand this interim, could you also talk about and maybe put some numbers around the possible sample site adjustment ranges based on the pre-specified plan? How long would that take at the maximum, if you decide to increase the size and let's say, you go with the max number of patients that are allowed? How long will that take?

Yes, absolutely. So I'll give as much as we feel that we could give right now in order like to preserve all the optionality for us. So the current steady state, I would say, of patients, right, the way we look into is not on the top of the screening, but on patients being randomized per week. So when you look into, what we can maintain confidently is anywhere between 20 and 30 patients per week randomized new patients. So if you fast forward to potential scenario here, so I'm going to use like two scenarios, right, an increase of 100, an increase of 200 patients, you can see that that could be achieved in like anywhere between like three to six weeks of randomization. Of course, you need 12 weeks after that to completion of the study. But it is very fast in terms of accruing new patients to the study if needed.

Thank you.

Of course.

Thank you. Our next question comes from Douglas Tsao with H.C. Wainwright. You may proceed.

Hi, good morning. Thanks for taking the question. Just to confirm, Marcio, what you just said. So I think you indicated 30 patients. Is that enrolled and randomized or is that simply enrolled into the study in the scenario that you expand the patient population for Essential3.

Yes. So that is what we very, very comfortable from, like phase of a randomization that we can achieve very, I would say relatively easily. I'm not going to say easily because there's a lot that goes on, on this randomized patients in a given week.

Okay. Okay, great. That's helpful. And then, just if you could provide a little more color in terms of moving from vormatrigine into these pain indications and what type of work you're going to be doing or need to do before coming out with a more sort of expansive or sort of coming forward with the full development plan.

Yes. So we're working and I'll say thanks for others working on this space, right? There's a lot that's been done on the last few years here as well. When you look into what's important for us, a couple of things, right? So one is the pharmacology itself, right? Like can we have the release of like, can you get your Cmax into relationships with Cmax like quickly enough for certain types of pain? What is the ideal types of pain? What is our confidence in terms of pre-clinically and potentially early clinical data, biomarker data, et cetera, that could get us to a point that we're incredibly competent as we were in epilepsy for when we like moving into a focal to have a similar package, I would say. And then like really understanding the impact where we're talking about here and I think differently from other things being developed, both central and peripheral aspects of the disease. So how much more can we expect from this mechanism? What is again ideal indication, ideal study to show that, that and cost in that study and things like that. So that's the works being done literally as we speak. A lot more should be finalized between now and the end of the year. And I think we're going to be in a very good position early in the year to showcase that to all of you.

Okay. Great. And then, just one more on Elsunersen. I think with last quarter you indicated that the first patient was being enrolled in sort of the global registration study, but I think today, you indicated that they're sort of being added to EMBRAVE. And I just want to understand if there's been any change as you think forward about the global registration program for that drug.

Yes. So that's a very important aspect as well. So the way we've been looking into Elsunersen about twofold here. So one, we consider to be important to explore particularly the safety at different exposure levels. And that's a lot of what's being done in Brazil right now. On the second Cohort is 1, 2, 3 randomized, like patient cohort to drug or placebo or to drug or chem [ph] on that case, we're exploring a range of dose sequentially increasing the dose on those patients. We're doing all the other assessments as well, as you can imagine. So it was important for us to actually keep that separated from what we believe to be a very good long-term efficacious exposure dose that is the 1 milligram per month for the global study. We have very good alignments already in general, what is needed there. But we do have still a meeting pending this year with the FDA on finalizing, which was likely changed on their end on the -- our expectations from when the meeting will occur. So nothing problematic there, but scheduling kind of drove the fact that we need just a little bit more time to make sure we have confidence on the final protocol, so we can initiate it. So that is the bottom line for that one.

Okay. And so with the patients being studied in Brazil now, are you -- you're looking at some additional doses, and if the result, I mean, is there a scenario? I know you've been very confident in the 1 mg/kg dose. I mean, is there a chance that if results warrant, that you would potentially look at higher doses in the U.S. and European registrational studies.

Yes. We must follow the science, right? So what we've seen so far on the patients in the U.S., which are continuing taking the drug, and on the patient in Europe and in Australia that, that actually took higher dose than in the U.S., it's not meaningfully different in terms of serial control gains on like development milestones and things like that. Now, we got to remain open to the possibility that, yes, it's going to be meaningfully different and meaningfully faster, whatever. And if that's the case, we would be in a position to complement the global study either in its open-label phase, right after the control phase, or even in a different cohort, if that is warranted. So we'll be driven by the results that we see here. But the timelines in terms of like the original four patients that are going to be dose there are perfectly aligned with the enrollment timeline we have for the global study. So it shouldn't be a complex in terms of how to get the best possible results for those patients.

Okay. Great. Thank you very much.

Thank you. Our next question comes from Kambiz Yazdi with Jefferies. You may proceed.

Good morning, team. A couple of questions for me. The placebo response was pretty well controlled in Essential1. Essential3 has a more innovated decentralized design. What steps have you taken to control placebo response in Study 1 in Essential3? And then, as a second kind of set of questions, maybe on vormatrigine, what have sodium channel blockers demonstrated historically in PGTC seizures? And what would a registrational program consist of in generalized epilepsy? Thank you.

Sure. Thanks, Kambiz. So placebo was already pretty well controlled, as you said on Essential1. When you look into Essential3, there was one aspect that, that we wanted to add to further control that. So what we're seeing is there is a, I would say slight but important change on patients that are less stable at baseline. And what I mean by that is, there were pre-screening assessments or -- sorry, pre-randomization assessments on study on Essential1 in a baseline assessment. So when you look into those patients that vary more in between those, they tended to be a little bit higher on placebo. Now, that study was again, at the end of the day, it's going to be like 4x smaller than Essential3. So we wanted to ask the question whether or not the influence is going to be similar, right? So we chose to actually add maximum variability parameter between those visits and to formally have as visits, the pre-randomization ones. We believe because you can monitor patients throughout the study, we know how long it takes for the drug to start working that we're very successful on controlling that, on making sure that the patients that are similar to what we want from E1, right? We don't want to depart from the cohorts, only one, but we want to make sure we tighten potentially variability that is not due to drug effect, but rather to placebo effect. So we're very, very confident on the measures that we put in place to control placebo there. And then, on your second question, on generalized, either primary or not, it makes the results historically and I think partially because that isn't really being a sodium channel blocker that is very selective and that really works on as these neurons are like firing a lot and expanding a lot in terms of like the loss of control. I'm going to call on the action potentials that can really block the pathological events, but not the physiological for these patients. That is a very good evidence with more selective or partially more selective drugs. So we are interesting enough, I would say anecdotally the conversations that we've been having, like a lot of the conversations that as studies get off the ground and sites get excited, a lot of people are equally or more excited actually about the generalized. What was a little bit surprising to me that there is so much excitement on generalized with vormatrigine and I believe it's because there is a huge amenity there and obviously those seizures are incredibly important as well, what they happen from a severity and potential impact and in terms of fatality as well for this patient. So we're going to see soon enough, I would say from RADIANT what kind of impact we can have there. And RADIANT is going to serve as a kind of springboard for us and to design what we would expect to be a registrational phase study for generalize as well.

Great. Thank you.

Of course.

Thank you. Our next question comes from Ami Fadia with Needham. You may proceed.

Hi, good morning. Thanks for all the updates. A couple of quick questions for me. Firstly on ulixa, can you comment on the enrollment and how -- what percent of patients have completed randomization relative to the target enrollment for the two studies? And was there a slowdown in the enrollment rate that caused the shift in the timeline? Maybe I'll ask my next question after you answer this one.

Sure. So Ami, we're not going to talk about that right now, as we mentioned, right, on the prepared remarks and in the press release. But what I can tell you that is no slowdown on what we expected from randomization or from patients on screening. I think we continue and we saw historically we expected to continue to see, if we decide to increase the size of the study in Q1, a fairly robust number of patients coming through. I think we intentionally been managing that, so we can get like the best possible outcome for the studies. There are two positive studies, like right after the entrance. So it's been a lot on us and of course, the scheduling of patients and things like that, which influence, but not a meaningful.

Got it. Okay. And then on vormatrigine in the RADIANT study, can you talk about how many patients you're targeting or sort of the mix of patients between focal and generalized and how that might inform your plans to develop it further in generalized epilepsy?

Yes. So the goal is to have 50 patients on RADIANT. What we are seeing again on early days, but what we are seeing is about like the expected 30% generalized, 70% focal interest for like in general, particularly like on the sites we targeted here we were, I would say, relatively selective in terms of the number of sites because that is again a huge interest and we didn't want to completely, I'm going to say, lose control of the number of patients and get significantly more than we expect here. So we kept that a little bit tight in terms of the 50 or so patients that we expect to enroll. That should be sufficient as we go like across and it's an open-label study, right? So continuously seeing and adapt as needed in terms of maybe reducing or increasing the total number of patients based on the overall interest. But 30, 70 from generalized and focal is what we're going to expect to see at the end.

Understood. Maybe just a last question from me. As you design the DEE study, what assumptions would you be making with regards to regulatory performance in this patient population relative to the data that you saw SCN2A and 8A?

Yes. So arguably SCN2A and 8A were the hardest of those conditions to treat. When you look across the board, yes, there are few other DEEs that incredibly difficult to treat, but those were definitely incredibly hard to see reduction to see seizure freedom mortality in 2A, for example, is like 6x higher than that, right, so in infancy, so this is significantly like higher bar. So we expect X or above the efficacy levels that we're seeing, of course, not powering this study for that. We're being a little bit more conservative, but I don't think it's unreasonable to assume that this would be best-in-class for these patients.

Thank you.

Thank you.

Thank you. Our next question comes from Joel Beatty with Baird. You may proceed.

Hey, thanks for the updates. The first one is on ulixacaltamide. If the interim is successful, could we get final results at that same time that we learned the interim was successful or will there inherently be some amount of time between those two events?

Yes. No, Joe, like thanks for that. The Elsunersen is successful. So if the boundary for an equivocal efficacy is crossed, we will have results at the same time.

Thanks. And then in DEEs, should we think about relutrigine as kind of just working in patients who are already responsive to calcium channel blockers? Or could you talk about the potential to work beyond DEE patients who are responsive to those agents?

Yes. So it's quite interesting. I think that is like when you look into pre-clinically and all the work we did. It does not look like it could or should be restrictive to patients who had prior response or that are expected to. If you look into all the work we did with the two compounds published a little back, the results on actual the dynamics of the neurons among the animal models, for example in Dravet syndrome are quite as the authors put unexpected meaning are significantly better than you would expect on that, which is there is a bias towards maybe some first generation sodium channel blockers wouldn't work on that population, right? So clearly not the case here. And then there's a few other ideas that we wouldn't -- our priority expect to have efficacy that we've seen efficacy on preclinical models and therefore, we should expect to have as well. When a seizure is happening, right, if we could observe like the neuron, sodium channels are going crazy, and then in a very late term way to describe it. So it stopping that activity is very, very important for seizure control independently of the etiology of the seizure or general even origin in the brain anatomically. So we expect quite wide range here of efficacy. I think what we have to ask the question as well is how consistent is the seizure? Because we want to count them similarly, right? We're going to do one study. It can't be, for example, some patients have clusters, others don't have clusters, so we shouldn't be putting them together. So that's more of a restriction than anything else.

Thank you.

Thank you.

Thank you. [Operator Instructions]. Our next question comes from Laura Chico with Wedbush Securities. You may proceed.

Hey, good morning, very much. Thanks for taking the question. Two clarification questions for me. First, on the interim for ulixacaltamide. I understand that the timing for the interim has extended to the first quarter 2025. What I'm trying to clarify though is does the actual at which the interim is executed, is that also changing? And I guess, maybe asking it differently if this was expected to be conducted at 50% for example, does this now shift to 60%? Hopefully that makes sense and then I have a follow-up.

Yes. It makes a lot of sense. Thanks for the question, Laura. Now, so the range that we gave for the information fraction, right, that if I understand correctly that's your question was between 50% and 75%. So the range for the information does not change. Of course, it is a range because like depends on the exact day of the data transfer and the calculations by the IDMC. But we did not change that.

Okay. That's helpful. And then, I guess, I understand your comments also about with respect to study conduct and integrity and the ramifications to Study 2. My understanding was that these are conducted under the same protocol. So I'm trying to understand the separation of the release of results. And have you had any feedback from FDA on how they would like to see results communication? Thanks.

Yes. So the last part is easy. So we did not and I don't think they often opine on how results should be communicated. They did though review the integrated statistical analysis plan, which analyzed these studies separately. And then there's another -- yet another analysis plan just for the interim analysis. So that, that was revealed and we received it back many months ago from the FDA on that. So a cover of that. So the influence is less operational. The [indiscernible] expenses like definition of operation meaning you are absolutely correct. These studies are randomized. Patients are randomized to one study or two the other. It's more on the influence of potential impression of failure by patients who are on Study 2 as they finalize a study by a potential news, since they wouldn't know their own Study 2 or Study 1. So we didn't do unduly influence or create quasi placebo effect by potentially in the positive case to be perfectly honest here creating a potential impact on what we expect to be applied successfully studied as a Study 2. So maybe overly cautious on our end but again trying to safeguard the integrity of the entire program.

Okay. That's helpful, Marcio. Maybe last question for me, I think I missed this and I know you commented that on earlier but could you expand a little bit more on the rationale the restart in the Parkinson's indication? I guess, I'm trying to better understand what would be the mechanistic read through from the ET studies to Parkinson's. Thanks very much.

Yes. No, no, absolutely. So I think from a scientific rationale was very strong to begin within Parkinson's, right, where the last time when we actually stopped the Parkinson's study had very little to do with our expectation in terms of results for that study and a lot to do with availability of capital. I think as we fast forward that we have significantly more safety data, of course, we are excited and we expect the Study 1 and Study 2 to be positive for Essential Tremor. The data from a scientific standpoint did not get weaker. They got stronger from a Parkinson's rationale. So why are not going to be like using significant amount of capital to actually reinitiate before the results. We want to be ready at the time of the Essential3 results to reinitiate Parkinson's. So maybe that's more of the message there than to have a delay and not necessarily use the mechanism. I think there's a far that is both a go-to-market strategy here where while movement disorder specialists only have about 5% to 10% of the patients, those 5% to 10% of the patients coexist a lot more with Parkinson patients. So that is a kind of a penetration of the market strategy that is important and the other is just engagement in general get some leaders out. Of course, it goes without saying that we think we can have a meaningful impact on Parkinson patients as well.

Thanks very much.

Of course.

Thank you. I would now like to turn the call back over to Marcio Souza for any closing remarks.

Thank you so much. I really appreciate everyone joining the call and staying with us, as the company continued to evolve quite positively, a lot went on over the last 10 months and 9 months into accounts departure in terms of the transformation of the company for what is going to be next year for registrational programs and potentially one NDA submitted mid-year or so for ulixacaltamide. As we continue to progress, millions of patients will be positively impacted by those drugs and billions of dollars in value are going to be created to all of us shareholders. So we appreciate it. Looking forward to providing more updates in the near future and I'm sure you're going to be in touch. Thank you so much.