Praxis Precision Medicines - Q3 2024

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines Q3 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 speaker's presentation, there will be a question-and-answer session. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. I would now like to hand the conference over to your speaker today, Dan Ferry from LifeSci.

Dan Ferry (Head of Investor Relations)

Good morning, and welcome to the Praxis Precision Medicines Q3 2024 financial results and business update conference call. This call is being webcast live and can be accessed on the investor section of the 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's views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future but is not taking on an obligation to do so. Please refer to Praxis's most recent filings with the Securities and Exchange Commission for 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.

Marcio Souza (CEO)

Thank you. Good morning and welcome to the Praxis Q3 2024 conference call. This past quarter, we remained laser-focused on advancing our pipeline as we gear up for next year to have four programs in registration, totaling to a substantial multi-billion dollar opportunity. The phase III 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 II EMBOLD trial in SCN2A and SCN8A GEs. In the 15-patient study, relutrigine demonstrated an impressive 46% reduction in moderate seizures versus placebo, with one-third of the patients achieving an unprecedented seizure-free status. Based on those results, we initiated a second registration of cohorts of the EMBOLD study, which has already started screening patients just weeks after completion of the prior cohorts. In common epilepsies, vermetrogene, previously known as Praxis 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 II RADIANT and the phase II/III POWER 1 trials are on track for top-line results next year. Rounding out our portfolio, elsanursen began 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 US 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 ulixacaltamide. Our innovative Essential3 program in ET is the biggest and most comprehensive program conducted today. We began recruiting for the two phase III studies just about one year ago and have seen tens of thousands of patients interested in participating.

This vibrant participation highlights the significant unmet needs for the millions of patients with essential tremor and 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 continue 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 III 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 activities of daily living, and they are both run entirely decentralized in the patient's home rather than at a clinical site. We shared on our last quarterly call that we decided to trigger a pre-planned interim analysis when 50%-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 ceasing 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 the study, cleaning of the data, execution of the statistical testing and analysis by independent boards and our internal operations, as well as considering the operational impact in the study completion of Study 2, we'll 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 readout of Study 1 and Study 2 until we hear from the interim 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. vermetrogene, 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 PRAX-628 will provide a highly differentiated, paradigm-shifting way to treat this disease. Last quarter, we introduced our broad ENERGY clinical program for PRAX-628 in focal and generalized epilepsies, and I'm glad to share that the ambitious multi-study goal we aim to achieve is 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 PRAX-628. Three trials of ENERGY are to evaluate the efficacy and safety. The first of these is RADIANT, an open-label study that will enroll patients with either focal or generalized epilepsy who will receive PRAX-628 for eight weeks with a safe 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 PRAX-628 and its pharmacology in the patient population. The POWER 1 and POWER 2 studies are 12-week phase II/III studies in patients with focal onset seizures. POWER 1 is underway, and we anticipate top-line results towards the end of 2025. We will likely stagger the initiation of POWER 2 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 PRAX-628 can play an important role, it's clear that its activity in NaV1.7 and NaV1.8, coupled with fast-acting pharmacology and safe profile, could play an important role in pain management.

We are concluding our assessments about the potential role of vermetrogene in pain, and we'll be sharing more in the near future. Now, turning to our relutrigine, a functioning state modulator that is formulated for pediatric use in DEs, 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 DEs, 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 parallel results we observed in phase II EMBOLD trial cohort one in SCN2A and 8A last quarter, where relutrigine for the other three periods, and neither the patient or investigators were aware which period was on placebo. 15 patients completed the study, and patients had the option to continue to an open-label extension after the 16 weeks.

A robust 46% placebo-adjusted reduction in moderate seizures over the period was observed, with 33% or five out of 15 patients achieving seizure-free status that notably was never seen before in this severe patient population. In addition, we saw a disease-modifying impact noted in the study by both caregivers and clinicians, with relutrigine leading to meaningful improvements in overall well-being of patients in areas of seizure severity and intensity, alertness, and other important measures.

This is also very impressive and encouraging finding given not only the severity of the disease but also the lack of improvement in these areas with currently available treatments. Lastly, relutrigine was generally well tolerated with no drug-related serious adverse events or dose reductions required during the study. These results further set up relutrigine as the potential first and best-in-class treatment, and following the successful proof of concept, we initiated screening for cohort two of the 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 DEs, which affect nearly 200,000 people in the U.S., 70%-80% of the patients are currently on a sodium channel block.

When we see the data from relutrigine, which used a more targeted approach on the sodium channel mechanism of action, we believe there is a broader potential for relutrigine across all DEs. With that in mind, we're already diligently working with the regulatory agencies to finalize the EMERALD study protocol for all DEs. 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, vermetrogene and relutrigine, and there's a lot more to come in 2025. Rounding out our clinical epilepsy program is our first ASO, elsanursen, designed to selectively decrease expression of the SCN2A gene and directly target the underlying cause in early onset seizures in SCN2A DE. Last quarter, we continued part A of the EMBRAVE protocol in Brazil.

This part of the study will provide important control data examining the safety and effectiveness of elsanursen 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 in 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?

Tim Kelly (CFO)

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's follow-on public offerings earlier this year. Our cash supports a 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. Now, we're open the call for Q&A, operator. Thank you.

Operator (participant)

As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. One moment for questions. Our first question comes from Ritu Baral with TD Cowen. You may proceed.

Ritu Baral (Analyst)

Good morning, guys. Thanks for taking the question. A couple of questions on relutrigine 562 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 expect it 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 two to change based on feedback and any specifics from what you're asking on EMERALD? Thanks.

Marcio Souza (CEO)

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, there are active patients. So we've been screening those patients in 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 half a milligram per kilogram per day, and this one is one milligram per kilogram per day. So it's 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 separation and a deeper effect, possibly maintaining or even expanding the number of seizure-free days and number of patients there. No real major 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 is what I would call. We're expecting to run a parallel group, one to one, 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 etiology.

For as long as they have no sensitivity to the 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 a number of 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.

Ritu Baral (Analyst)

That is right. Okay. Got it. Thank you. Thank you.

Operator (participant)

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

Yasmeen Rahimi (Analyst)

Good morning, Tim. Thank you so much for all the thoughtful comments.

A 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 the study two will not read out before the interim, or at the interim, we'll get an insight about one and two. 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 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 the success in AT would move you into Parkinson's, or would that be a phase II study, phase III study? Any color around that would be helpful, and I'll jump back into the queue.

Tim Kelly (CFO)

Sounds good. Thanks, yes. So starting on the interim, right? So I'll start by saying we're very confident on the execution for the interim. Every aspect that we're monitoring and every discussion just increased our confidence on a successful execution. Of course, it is biased towards success to begin with and making sure we wrap up the program concomitantly to slash shortly thereafter to the interim. And that was, 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 relutrigine hydrochloride for these patients. When you look into that, there was a number of things that were either bumping up in terms of availability of IDMC members, their ability to conduct the analysis, cleaning of the data. And I would argue the most important factor here is the influence on study two. That is the second part of your question, right? In the eventuality, which is quite a possibility, that the interim analysis worked exactly as we expect, so very positive. We wanted to make sure the readout of study two is about the same time to shortly thereafter, number one.

But two, that there is no influence, and by influence, I mean negative influence on study two readouts. So when you're looking into it as a program, it made sense for us to make this, which in our view is a small and slight change that is safeguarding the overall positive results in our view of the combined studies, right? Study one, study two, its combination, and the package for the NDA. So that is the main rationale on our end. Everything is progressing brilliantly so far. Then 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 for the expansion, right? Time is an incredibly important asset on this business. We want to make sure that an indication of value for ourselves, for potential strategics, and so on and so forth gets off the ground.

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 II/III 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 in epilepsy instead of just one.

Yasmeen Rahimi (Analyst)

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

Operator (participant)

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

Joon Lee (Analyst)

Hey, thanks for the updates, guys. Just a quick clarification. Will you be including Lennox-Gastaut in the broader DEE study?

Because there's really 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.

Marcio Souza (CEO)

Sounds good. We will include LGS patients on this who attempted to answer again to Ritu before. We are attempting to collect as much genotype information. Sometimes, as you know, they're going to be phenotypically defined, clinically defined, and not have a final diagnosis there. But we believe that as these patients are right now, when you look into actual data on the literature, on claims data for LGS, it's one of the highest use of the 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 that.

At the same time, that is part of this entire discussion about inclusion criteria and measuring is the discussion we're having right now.

Joon Lee (Analyst)

Great. So it's a true DEE study. Great. For the interim analysis for essential program, just wanted to clarify that when you refer to interim analysis, you're referring to the study one interim. So your randomized withdrawal trial top line will depend on the interim from the parallel comparator trial. Is that correct? And then is yeah. No, go ahead. I'm sorry. Yeah. And then part two is that is there or is there no inferiority analysis baked into that interim analysis?

Marcio Souza (CEO)

Yeah. So the interim analysis is on study one only, as you mentioned, right? We don't believe that would be necessary or appropriate for an interim on study two.

Basically, there's an alignment in terms of database lock cleaning between the multiple events that we're talking here. So that could be somewhat of an influence because those studies are recruited concomitantly, right? As you know, from the same pool of patients, and they are randomized to these 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 two, of course, shortly thereafter on the interim. That is an easier, one could argue, study to monitor based on 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 futility margin on the lower end of the conditional power as is the standard, right, on interims like that.

So, fairly standard in terms of the bottom there, a fairly wide, I would say, sample size of the estimation zone because that is 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. We wanted to balance all of that, of course, from an information fraction perspective and from a spending perspective and the overall execution to drive toward the successful outcome.

Joon Lee (Analyst)

Great. And then last question. As we look to the very likely approval of suzetrigine from Vertex 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.

It's actually interesting that you're looking at your NaV1.7 and NaV1.8 targeting 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 I or any other studies? Thank you.

Marcio Souza (CEO)

Yeah. We're super excited about this as well. We've been looking for a while. It's not something that made sense from a priority, execution, and capital allocation standpoint beforehand for us, but now we believe it does. We do have very strong preclinical evidence in pain models and in general, very potent inhibitor of NaV1.7 and NaV1.8, as you know. That mechanism and the duality of the mechanism is quite important in pain generally, acute and subchronic and chronic pain. We thought that, yep, we're excited with what we're seeing.

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 would be competitive, and then talk about a plan early in the year with all of you.

Joon Lee (Analyst)

Thanks for all your answers. Of course. Thank you.

Operator (participant)

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

François Brisebois (Analyst)

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 one on study two. 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 one will be after study two that might come short after the interim look? Just any help there understanding the timeline of the top line versus the interim for study one?

Marcio Souza (CEO)

Yeah. Sounds good. Thank you. So I think the scenario is like if I think about boot camps here. So one, as you mentioned, the potential to stop 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 one and study two at that point in time, which obviously would be quite positive, complete package, and so on. I think that is now an opportunity as well to increase the size of study one.

In that case, the conversation we'll be having is we're moving study one forward, we're increasing the size, and for study two, we should have the results very quickly as well. So that's when it dissociates the two. That is the highest 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's the two I would say we should plan the most around with the first one having the highest impact, right, in terms of operationally making sure we're ready to wrap it up, the other two studies, and so on. So that's one of the considerations and how we're looking 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? Yeah. 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 about 30% outside of the U.S. for a peak. We're talking about a multi-billion dollar peak here in DEEs, right?

We just completed yet 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 the potential peak 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, it's important to have access to patients as well, but not as important to get the drug off the ground and get to quite meaningful revenue. So about 2/3 in the U.S., 1/3 outside of the U.S., that's how we've been modeling.

François Brisebois (Analyst)

Thank you. Thank you.

Operator (participant)

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

Yatin Suneja (Analyst)

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 and how many patients have been enrolled in study one and two if you could? And then we understand this interim. Could you also talk about and maybe put some numbers around the possible sample size 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? Thank you.

Marcio Souza (CEO)

Yeah. Absolutely. So I'll give as much as we feel that we could give right now in order to preserve 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, it's 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 two scenarios, right? An increase of 100, an increase of 200 patients.

You can see that that could be achieved in anywhere between 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.

Yatin Suneja (Analyst)

Thank you. Of course.

Operator (participant)

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

Douglas Tsao (Analyst)

Hi. Good morning. Thanks for taking the questions. 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 essential three?

Marcio Souza (CEO)

Yeah. So that is what we're very, very comfortable from our base of our 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.

Douglas Tsao (Analyst)

Okay. Okay. Great. That's helpful. And then just if you could provide a little more color in terms of moving from epilepsy 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 expansion or sort of coming forward with the full development plan.

Marcio Souza (CEO)

Yeah. So we're working on it, and I would say thanks to others working on this space, right? There's a lot that's been done in 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?

Can we have the relief? Can you get to CNS and to relationships with CNS quickly enough for certain types of pain? What is the ideal types of pain? What is our confidence in terms of preclinically and potentially early clinical data, biomarker data, etc., that could get us to a point that we're incredibly confident that we were in that class for when we're moving into a focal to have a similar package, I would say, and then 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 and cost of that study and things like that, so that's the work being done literally as we speak.

A lot more to 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.

Douglas Tsao (Analyst)

Okay. Great. And then just one more on elsanursen. I think with last quarter, you indicated that the first patient was being enrolled in sort of a 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.

Marcio Souza (CEO)

Yeah. So no, that's a very important aspect as well. So the way we've been looking into elsanursen is two-fold here. So one, we consider it 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 one, two, three randomized patient cohort to drug or placebo or to drug or sham on that case. We're exploring a range of those 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 one milligram per month for the global study. We have very good alignments already in general on 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 or on our expectations from when the meeting would 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.

Douglas Tsao (Analyst)

Okay. And so with the patients being studied in Brazil now, 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 one milligram per kg dose. I mean, is there a chance that if results warrant that you would potentially look at higher doses in the US and European registrational studies?

Marcio Souza (CEO)

Yeah. We must follow the science, right?

So what we've seen so far on the patients in the US, which are continuing taking the drug, and on the patient in Europe and in Australia that actually took higher dose than in the US, it's not meaningfully different in terms of seizure control, gains on development milestones, and things like that. Now, we've 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 the original four patients that are going to be dosed there are perfectly aligned with the enrollment timelines we have for the global study. So it shouldn't be a conflict in terms of how to get to the best possible result for those patients.

Kambiz Yazdi (Analyst)

Okay. Great. Thank you very much.

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

Morning, team. A couple of questions for me. The placebo response was pretty well controlled in Essential1. Essential3 has a more innovative 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 vermetrogene, what have sodium channel blockers demonstrated historically in PGTC seizures? And what would a registrational program consist of in generalized epilepsy? Thank you.

Marcio Souza (CEO)

Sure. Thanks, Kevin.

So placebo was already pretty well controlled, as you said, on Essential1. When you look into Essential3, there was one aspect that we wanted to add to further control that. So what we've seen is there is, I would say, a 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, a pre-randomization assessment on Essential1 and 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 was going to be similar, right?

So we chose to actually add maximum variability parameter between those visits and to formally have end 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 were 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 on E1, 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's mixed the results historically.

I think partially because there isn't really being a sodium channel blocker that is very selective and that really works on as these neurons are firing a lot and expanding a lot in terms of the loss of control over the action potentials that can really block the pathological events, but not the physiological for these patients. That is very good evidence with more selective or partially more selective drugs. Interestingly 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 one. It was a little bit surprising to me that there is so much excitement on generalized with vermetrogene. I believe it's because there is a huge unmet need there.

And obviously, those seizures are incredibly important as well when 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 generalized as well.

Kambiz Yazdi (Analyst)

Great. Thank you. Of course.

Operator (participant)

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

Ami Fadia (Analyst)

Hi. Good morning. Thanks for all the updates. A couple of quick questions for me. Firstly, on ulixacaltamide, can you comment on the enrollment and what percentage 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 on this one. Sure.

Marcio Souza (CEO)

Sure. So I mean, we're not going to talk about that right now, as you 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 the best possible outcome for the studies that are two positive studies right after the entrance. So it's been a lot on us.

And of course, the scheduling of patients and things like that, which influenced, but nothing meaningful.

Ami Fadia (Analyst)

Got it. Okay. And then on vermetrogene 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?

Marcio Souza (CEO)

Yeah. So the goal is to have 50 patients on RADIANT. What we are seeing, again, on the early days, but what we are seeing is about the expected 30% generalized, 70% focal interest for in general, particularly 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.

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 across. And it's an open label study, right? So we're going to continuously see 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.

Ami Fadia (Analyst)

Understood. Maybe just a last question from me. As you design the EMERALD study, what assumptions would you be making with regards to reduction performance in this patient population relative to the data that you saw in SCN2A and SCN8A? Yeah.

Marcio Souza (CEO)

So arguably, SCN2A and SCN8A were the hardest of those conditions to treat. When you look across the board, yeah, there are a few other diseases that are incredibly difficult to treat, but those were definitely incredibly hard to see reduction, to see seizure freedom. Mortality in SCN8A, for example, is like 6x higher than in infancy. So this is a significantly higher bar. So we expect 50% or above the efficacy levels that we're seeing, of course, not powering the 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.

Ami Fadia (Analyst)

Thank you. Thank you.

Operator (participant)

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

Joel Beatty (Analyst)

Thanks for the updates. The first one is on ulixacaltamide.

If the interim is successful, could we get final results at the same time that we learned the interim was successful, or will there inherently be some amount of time between those two events?

Marcio Souza (CEO)

Yeah. No, Joel, thanks for that. If the interim is successful, so if the boundary for an unequivocal efficacy is crossed, we will have results at the same time.

Joel Beatty (Analyst)

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?

Marcio Souza (CEO)

Yeah. So it's quite interesting. I think that is when you look into preclinically and other 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 actually 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 diseases that we wouldn't a priori expect to have efficacy that we're seeing efficacy on preclinical models, and therefore, we should expect to have as well. When a seizure is happening, right, if we could observe the neuron, sodium channels are going crazy. That's in a very lay term way to describe it.

So stopping that activity is very, very important for seizure control independently of the etiology of the seizure or generalized or 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 counsel them similarly, right? If 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 put them together. So that's more of a restriction than anything else.

Joel Beatty (Analyst)

Thank you. Thank you.

Operator (participant)

Thank you. And as a reminder, to ask a question, please press star one one on your telephone. Our next question comes from Laura Chico with Wedbush Securities. You may proceed.

Laura Chico (Analyst)

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 of 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.

Marcio Souza (CEO)

That makes a lot of sense. Thanks for the question, Laura. So the range that we gave for the information fraction, right, 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 it 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 two. 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 result communication?

Laura Chico (Analyst)

Thanks. Yeah. 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 yet another analysis plan just for the internal analysis. So that was reviewed, and we received feedback many months ago from the FDA on that or FDA on that.

Marcio Souza (CEO)

So the influence is less operational on the integrity assessment definition of operation, meaning you're absolutely correct. The studies are randomized. Patients are randomized to one study or to the other. It's more on the influence of potential impression of failure by patients who are on study two as they finalize the study by potential need less since they wouldn't know they're on study two or study one. So we didn't unduly influence or create quasi-placebo effects by potentially, in the positive case, to be perfectly honest here, creating a potential impact on what we expect to be a quite successful study that is a study two. So maybe overly cautious on our end, but again, trying to safeguard the integrity of the entire program.

Laura Chico (Analyst)

Okay. That's helpful, Marcio, and maybe last question for me.

I think I missed this, and I know you commented on it earlier, but could you expand a little bit more on the rationale and 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.

Marcio Souza (CEO)

Yeah. No, no, absolutely. So I think from a scientific rationale was very strong to begin with in Parkinson's, right? 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, then we have significantly more safety data. Of course, we are excited, and we expect the study one and study two 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 we not going to be using a 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 factor that is both a go-to-market strategy here where while movement disorder specialists only have about 5%-10% of the patients, those 5%-10% of the patients coexist a lot more with Parkinson's patients. So that is kind of a penetration of the market strategy that is important. And the other is just engagement in general of few opinion leaders. Of course, it goes without saying that we think we can have a meaningful impact on Parkinson's patients as well.

Laura Chico (Analyst)

Thanks very much. Of course.

Operator (participant)

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

Marcio Souza (CEO)

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 in the last 10 months and nine months, if you count the quarter, in terms of the transformation of the company for what is going to be next year for registration of 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 we're going to be in touch.

Operator (participant)

Thank you so much. Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.