PRAX - NASDAQ

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2025 Earnings Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Dan Ferry, Investor Relations. Please go ahead.

Good morning, and welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2025 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 time lines 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 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 us on today's call are Marcio De'Souza, President and Chief Executive Officer of Praxis; and Tim Kelly, our Chief Financial Officer. After updates on our key programs, we'll move to a brief Q&A session, where Marcio and Tim will be joined by Steve Petrou, President of Research and Development; and Megan Sniecinski, Chief Operating Officer. With that, it's my pleasure to turn the call over to Marcio.

Thank you, Dan. Good morning, and thank you for joining the Praxis Fourth Quarter 2025 Conference Call. Let me start by saying that 2025 was a remarkable year for Praxis. It was marked with the breadth of significant clinical achievements and regulatory advance across our portfolio with positive readouts and FDA interactions for ulixacaltamide, relutrigine and vormatrigine as well as accelerated development plan for elsunersen. Standing here today, we deliver on our goal to submit two NDAs one for ulixacaltamide in essential tremor and one for relutrigine in SCN2A and 8A DEEs. Just like 2025, this year will continue to enhance our clinical portfolio and mark our transformation into a commercial company. Next quarter, we expect to have the top line results for POWER1 for vormatrigine in focal epilepsy and the elsunersen EMBRAVE data. In the second half of the year, we expect to complete enrollment for POWER2. The EMERALD trial for relutrigine in broad disease is expected to serve as the base of an sNDA by next year. And those are only a fraction of the deliverables expected in the next 12 months. We have the drugs, the people and the capital to deliver yet another transformational year, bringing innovative treatment to patients with CNS disorders. Let me now deep dive a little bit on each one of the clinical programs. Now focusing on ulixacaltamide. Last October, we reported the positive top line results from the Essential3 program with both studies delivering clinically meaningful and statistically significant results. Study 1 met its primary and all key secondary endpoints with ulixa showing meaningful improvements in the mADL11 in the rate of disease progress, PGI and CGI. Study 2 also met its prespecified primary endpoint with ulixa demonstrating a superior maintenance of effects during the randomized withdrawal phase. This was the first time an investigational therapy designed specifically for patients with ET showed positive results in a comprehensive clinical program. Based on this positive data and the fact that there is no other specific therapy delivering such results as ulixacaltamide, we have granted breakthrough designation by the FDA in December. Had a very productive pre-NDA meeting in December with the FDA and worked diligently to prepare the NDA submission. We have recently completed the NDA submission to the FDA. Now as we move towards expecting an approval in the near future, our preparations for the commercial launch for ulixacaltamide are well underway. We estimate that more than 7 million people in the United States live with essential tremor with about 2 million of them being an immediate need for therapy or an addressable population, as we call. And we're excited about the opportunity to deliver a therapy that can meaningfully improve their daily lives. As we interact with more neurologists in this space, we continue to hear this a drug that meets a large unmet need in their practice and their interest continues to improve towards the potential use of ulixacaltamide when available in the future. We believe ulixacaltamide has a big potential of over $10 billion annually. Given the size of the population, the strength of the clinical data, the opportunity for responsible pricing that recognize the value of the drug, we have been building our commercial organization infrastructure, including key hires and core aspects of the prelaunch plan, including preparing a comprehensive medical education campaign, which we plan to launch at the upcoming American Academy of Neurology Annual Meeting in April. At AAN, we also share additional data from the Essential3 studies in multiple presentations. We look forward to interacting with our core IDNs in Chicago next quarter and share the exciting data from the Essential3 program. Moving on to our epilepsy programs. We started the discussion with our relutrigine program in developmental and epileptic encephalopathies, a group of severe epilepsies characterized by developmental delays with early onset for which there are limited to no currently approved treatments. In December, at the Annual Meeting of the American Epilepsy Society, we presented data from the EMBOLD study in SCN2A and 8A DEEs. We delivered overwhelming efficacy with relutrigine treatment leading to a clinically meaningful and statistically significant change in seizure and associated developmental endpoints like disruptive behavior, alertness and communication. Beyond the impressive overall results, the effect of relutrigine was rapid, durable and continue to deepen with time. Given the strong efficacy results and the favorable safety profile, underscoring relutrigine best-in-class potential and alignment with the FDA, we have submitted the NDA earlier this year. It's worth mentioning that relutrigine has rare pediatric drug designation, making it eligible for the pediatric review voucher program upon approval. The initial addressable population for relutrigine for SCN2A and 8A DEEs is roughly 10,000 patients in the U.S. However, there are currently over 200,000 patients with DEE for which we believe relutrigine could offer benefits. The ongoing EMBOLD study is assessing relutrigine in the broader DEE population and we are on track to complete enrollment in this study this year. If the NDA in SCN2A and 8A we just submitted is approved and the EMBOLD study is positive, we expect to submit a supplemental NDA for the treatment of broad disease by 2027. We believe the full potential of relutrigine in DEE space could be as large as $5 billion in annual revenue. Similarly to the efforts for ulixacaltamide in essential tremor, we have initiated prelaunch activities, including key hires and building sufficient inventory for a successful expected launch of relutrigine. Our team has been accelerating the efforts to ensure patients have access to this potential first disease-modifying treatment for SCN2A and SCN8A. Moving on to vormatrigine. Our comprehensive ENERGY program for vormatrigine, a next-generation functionally selective small molecule in development as a once-day treatment for adults with common epilepsies. At the December AES meeting, we shared the full data from our RADIANT Phase III study, where vormatrigine demonstrated its best-in-disease potential in patients with focal onset seizures. Vormatrigine had fast-acting efficacy with 58% of patients achieving at least 50% reduction in seizures at week 1 without the need for titration. This effect continues to increase with patients who proceed to the OLE were achieving 100% median weekly seizure reduction at week 9, which was sustained through week 16. Additionally, we saw the vormatrigine improved efficacy on top of other common antiseizure medications patients were taking. We are on track for multiple readouts from the pivotal studies for vormatrigine in the next 12 to 18 months. The next clinical update will be for POWER1, our study in focal onset seizures, which exceeded its original enrollment targets. We expect to share the top line results in the second quarter of this year. The second Phase III study, POWER2, has been enrolling patients and we anticipate enrollment to be completed by the end of the year. Those two studies, if successful, will serve as the base of a new drug application for vormatrigine. We're also on track to initiate the POWER3 study, which will evaluate vormatrigine as a monotherapy in the first half of this year as well. Altogether, it's a very robust registrational program that we believe will demonstrate vormatrigine's potential to address the significant unmet needs of approximately 3 million people in the United States suffering from common epilepsies, potential to achieve over $4 billion in annual revenue. Turning on to our fourth program in the clinic, elsunersen. Elsunersen is being developed for the treatment of gain-of-function at SCN2A DEE, a rare genetic epilepsy characterized by early onset seizures and very detrimental developmental impact. This past December, we have had a favorable meeting with the FDA where the agency agreed to update the EMBRAVE3 registrational trial design, simplifying it by converting from the double-blind sham control design to a single-arm baseline controlled study where approximately 30 patients will be enrolled. We are quickly enrolling this study and expect it to be completed later this year with a potential NDA for elsunersen next year. While EMBRAVE3 is enrolling, we'll have some additional data from the EMBRAVE study Part A, our Phase I/II study evaluating the safety and efficacy of elsunersen versus sham procedure. The trial is ongoing and are on track to report the top line results from the original nine patients in the first half of this year. Elsunersen also has rare pediatric drug designation and we qualify for a pediatric review voucher upon approval. Once approved, we believe elsunersen has the potential for over $1 billion in annual revenue. In summary, 2025 was a year of major portfolio advancements as we enter our pre-commercial phase. We started 2026 strong with two NDA submissions, and we're positioned for another catalyst-rich year with multiple readouts of our innovative pipeline. We are planning an R&D Day next quarter to discuss our clinical programs and preclinical programs and a commercial day to follow where we highlight our launch strategy, readiness and more aspects of the launch for ulixacaltamide and relutrigine. With a very strong balance sheet, we're well capitalized and focused on discipline of execution to deliver on the preclinical, clinical and pre-commercial activities this year to come. while unlocking the more than $20 billion of opportunities across our comprehensive CNS portfolio. With that, I'll hand over our call to our CFO, Tim Kelly. Tim?

Thanks, Marcio. Good morning, everybody, and thank you for joining today's call. I'll provide a quick summary of our fourth quarter and full year financial results. 2025 was a year of continued investment into the pipeline while maintaining rigorous financial stewardship. In Q4, operating expenses totaled $97 million, broken down to $77.5 million for R&D and $19.5 million for G&A. That compares to Q4 of 2024, where total operating expenses were $71.4 million, broken down to $56.3 million for R&D and $15.1 million for G&A. For the full year, operating expenses totaled $326 million for 2025 compared to $209 million for 2024. The increases in both Q4 and full year were driven by an increased spend in our Cerebrum and Solidus platforms to progress the portfolio of clinical programs. As we go into 2026, we expect to have a significant increase in spend as we invest into our commercial launch activities that Marcio just discussed as well as continuing to progress the pipeline. We ended Q4 with $926 million in cash, equivalents and marketable securities compared to $469 million as of December 31, 2024. This increase of $457 million was primarily due to net proceeds from Praxis October 25 follow-on public offering and net proceeds from the at-the-market sales of common stock offset by cash used in operations. Our cash position was further strengthened through proceeds from a public offering in January this year, which yielded $621 million. When added to our year-end position, our pro forma cash is approximately $1.5 billion, which is expected to fund operations into 2028. With that, I will pass it back over to you, Marcio.

Thank you, Tim. We're going to now open the call for Q&A. Shannon, would you compile the queue, please?

[Operator Instructions] Our first question comes from the line of Yasmeen Rahimi with Piper Sandler.

Congrats to the outstanding timing of the filing. So congrats. Two questions, one directed to Tim and one for Marcio. Tim, if you could maybe walk us through the pre-commercial activities that are going on currently and what the cadence are going to be throughout 2026. That's very helpful. And then for Marcio, maybe help us understand sort of what additional new data we could be seeing at AAN, and I'll jump back into the queue for respect to my colleagues to ask questions.

Yes. Thanks very much, Yas. And glad to be talking about what we're doing to prepare for two launches. As you can imagine, we're at the stage now where we're making some key hires and looking to build out the talent for our commercial organization. We've also been focusing on ensuring that we have sufficient inventory for what we expect will be good strong launches, and we never want to run out and be sure that we've got inventory on hand for all scenarios. That's a long lead time activity, so very well in hand to ensure that, that's in good shape. And then also looking at for -- particularly for ulixacaltamide, helping to improve awareness of the disease. And Marcio in a moment will talk about our activities at AAN and all the data we're sharing there. We're also looking at that at a time when we can start sharing more about the disease and help patients understand about the innovative therapies we're developing.

Yes. Thanks, Tim. That's a lot going on, as you mentioned, right, in terms of making sure that not only the highest quality NDAs were submitted as, of course, was always our priority, but now moving on to making sure a smooth review with the agency. And then on the other side of that, the prescribers really understand or potential prescribers really understand the disease in one hand, which they understand well, but there's obviously a good reminder there. And on the other hand, the clinical data for ulixa and then relutrigine later in the year as well. In regards to the American Academy of Neurology meeting next quarter, we have about 15 different presentations going on at the meeting. It just speaks about the number of things across the company. A number of them are about the Essential3 program and essential tremor in general. What we're going to be doing there, as you will see, and I hope to see you there in Chicago is oral presentations on the clinical data. AAN actually is very nice for that because the presentations are reasonably long. So we can go into a fair bit of detail on the clinical program, which, of course, very important for the 13,000 or so neurologists that are our audience. They're going to be there also to expand the understanding on the overall community of this very strong clinical data set. So we're going to be discussing like other aspects like the response on the drug and what happens to these patients and just how meaningful it is the combination of all the endpoints, but particularly the primary measure here that's the mADL11. And you're going to see throughout all the presentations, there are very robust number of new data points. We put a lot out there. So it's not to say that there is any scarcity of data on the Essential3 program, but it is definitely more geared towards the future prescriber here that is the neurologist. So incredibly excited, very grateful to the scientific community of AAN to giving us the podium there to present the strong clinical data.

Our next question comes from the line of Ritu Baral with TD Cowen.

This is Athena Chin on for Ritu. I have another one on ulixa. You previously indicated that the label may include alternative titration schedules. What is the status on this? And are you currently running additional studies to support this? If the label doesn't include these schedules, how will you be educating and guiding prescribers upon launch? And then I have another follow-up.

Yes. Thanks, Athena. So maybe I'll break it down, if I may, your questions in two parts, right? So we've been discussing since you asked about education. And surprisingly, I would say there's very little education needed here. We've been presenting the data for advisory boards for consultation meetings to a number of key opinion leaders in the country, very top key opinion leaders. And it's very clear that they see this incredibly robust and very, very easy to deal with the potential tolerability for a subset of patients here that we know might have that. Now going back to the matter of the label, as we previously discussed, we proposed not only submitted proposed label to the FDA, not only the standards titration that was done in the clinical study, right? So seven days 20 milligrams, seven days at 40 and then seven days at a stable dose of 60, but also an alternative that we discussed with the FDA. I think as we move forward, as we continue to engage with the agency here, it's now their view has to prevail in terms of what the final label is going to be. So it would be pretentious to us to say what's going to happen there. But it came in the heels of discussions with them and alignment. The agency was incredibly clear with us that they did not expect us to conduct clinical studies preapproval on this regard. So as we always respect the opinion of the FDA and the guidance they give, of course, we're not doing. I believe, and now that's my interpretation, that is because this is really not a safety issue, right? That is some tolerability that happens on a subset of patients. It's very quick. It resolves very quickly. And the efficacy, most importantly, is very strong. So when you put from a benefit risk perspective, that is both our interest, the prescribers' interest and the agent's mandate that is all maintained quite nicely. We're going to see how this progress during the review, and we're very enthusiastic about the ability to have serving not only the 70% or so of patients that stay and do really well, but hopefully 100% of the patients that try this drug.

Got it. And as to the commercial prep for both relutrigine and ulixa, how much capital allocation should we be thinking about between the two programs?

I think in terms of allocation, you can imagine that with ulixa being a much broader market, we will be probably putting more of the allocation there. I think we're looking at, as I said, the disease awareness campaign, probably a bigger field force as we get into that part of the work as well. The inventory build is going to be a bit bigger. So we want to be sure I go back to the old line, you only get one chance to launch a drug, and we want to be sure we're investing appropriately for a great launch. I think with relutrigine, when we look at that market, particularly focused initially on the 2A and 8A population, it is a bit more focused. So there's a lot of disease awareness for us to be. Doing there. It's a more focused effort though with those physicians, but we want to be laying the groundwork for the indication expansion that we hope will come in 2027 with the EMERALD study. So it's a bit of a strategic move on how we will do the commercial prep for relutrigine also.

Our next question comes from the line of Yatin Suneja with Guggenheim.

I have two questions. With regard to the POWER3 study, can you just articulate to us how will that study help you move towards the frontline setting or to in FOS. So that's one. And then the second question is around the review time line. So we -- I think, Marcio, it will be good if you can address the review time line for both the NDAs. We do get questions from investors in terms of priority review or not. So it will be good to sort of address it today.

Yes. Thanks, Yatin. So starting with POWER3, right? So just a reminder of what we are trying to accomplish here. So POWER1 as the like first study here for -- towards registration for vormatrigine reading out as we just narrowed here in Q2. The study enrolled a fair bit more than the original 230 patients that were planned. So we're very, very happy with how enthusiastic the investigators were on enrolling patients on this study, particularly like when you consider competitively how well this study enrolls, right? Power2, as we're enrolling quite nicely right now as well, would be the second registrational. But when you look into the market, and it's something quite interesting what this goes on and on that features. You do have, I would say, a part of this market that is the more refractory patients or going to even argue hyper-refractory being super treated multiple ASMs really struggling for years and years, possibly decades here. And that's where most of drug development and most of what the Level 4 epilepsy centers, the key opinion leaders in epilepsy have been focusing. But when you go to the rest of the market, and it's probably a little physicians to call rest because it's the majority of the market, right, the patients that are 70%, 80% of the patients with focal onset seizures, they still can strive. They still can carry on with their lives. There's all sort of restrictions because they're having like breakthrough seizures from time to time, and they're really not doing well. That market has stayed untapped until now. So speaking with those physicians and people who treat a significant number of patients, right, which is a different subset of the ones we're looking. The need there is for a drug that they can trust and understand how to remove the treatments, so they can be confident and they are very enthusiastic about vormatrigine for that matter. So we've been in consultation with them finalizing the design. We're getting this off the ground very soon. We thought today was the day to reinforce and celebrate submitting two NDAs. So we're going to be talking about that more in the near future. But what it does to the drug, while not required for registration, right? This is not a requirement as is the ever-evolving requirement for registration in the United States as we are seeing this week. So we're very excited about what's to come. But it is something we can see as moving to first-line potentially this drug in the future, which is from a serving patients is what we all should be aiming for. We're just in a very privileged position that vormatrigine might be the drug that allows patients and physicians to do that. On your second question about the review time lines, you can imagine that the decisions we have to make are multiple fold, right? So, one, obviously, the timing of the submission is now in the past. The second is the entire understanding and relationship and workload and so forth with the agency. A good reminder here that DN1 or Division of Neurology I and II are two different divisions, there's a lot of shared resource. We're having two NDAs at the same time with them. Very obviously, relutrigine is easier. I'm going to say not because it's easier from a clinical or anything like that. It's just much, much less data by single study rare indication and that by itself from a workload perspective is smaller. So we decided to request a priority review for that application, but we decided not to request for ulixacaltamide for multiple reasons, right? Those that I just mentioned, but there's a broader business reason about the time of the launch and the maximization of the revenues over time for this drug, particularly around PIC, particularly around payer and overall dynamics of discounting and so on that happens here later in the launch. So on a drug that can be and will be as big as ulixacaltamide, we can't like pick up the dollars and forget about the millions on this one. So I think we need to be -- and we were very focused strategically on the overall value here.

Our next question comes from the line of Joon Lee with Truist Securities.

Congrats on all the progress. I just want to clarify the response from the prior question that you just answered. So you mentioned business reasons for not asking for priority review for ulixacaltamide in ET. Just to clarify, is that because asking for standard review as opposed to priority review would result in almost a year delay in being forced to negotiate under IRA? That's question number one. Question number two, looking forward to your presentations at AAN, can we expect any long-term follow-up data? The reason I ask is long-term efficacy came up as a key point for our payer KOLs regarding reauthorization of ulixa in ET. And the last question is, in the past, you telegraphed around $50,000 list price for ulixacaltamide. Is that still the case? And can you help us understand your thought process behind the pricing strategy?

Yes. Joon, I think you are in the right direction there, right, in terms of when you're looking at and we're forecasting this drug. Of course, there are multiple dynamics, and you just named some of them, right, like what payers and reauthorization and like potential step edits and you name it, but the Inflation Reduction Act and the dynamics of the Act right now is an important consideration as always a very important consideration. This is a heavily Medicare Part D population. So we want to make sure we're both responsible on how we're launching. We're also maximizing and giving the proper value for the drug. And that includes looking to the life cycle of evolution of the current iteration of the act when it impacts, when it kicks in, I believe that's where you're going there. There's a pretty big difference in value depending on when that negotiation happens. And it was a key consideration on our filing strategy. The second on the data to be presented, I think multiple fold, yes, we're always like going to be presenting more and more data to reinforce the short-term and long-term value of ulixacaltamide in essential tremor. One point we believe there's still room to explore here is really how strong the data is. I know you recently spoke to some payers and like payer groups. And they -- if I understand correctly, they agree with how strong this data is and how high the potential for this drug is. But it's what is the understanding is not clear yet in the market because we haven't put the data out there is just how deep the effect is on a very large proportion of patients. And when you look into drugs, it's not one size fits all. So we want to make sure that gets reinforced, that gets holistically reviewed. While we're very excited about having our principal investigators presenting this data to their peers. They've been thrilled with the execution, with the results. And I think now is the time to let them take the stage and present this data as key opinion leaders in the field. So stay tuned. I know we're trying to cover a lot in this call, but stay tuned for April. I'm sure we're going to be pleased.

Our next question comes from the line of Andrew Tsai with Jefferies.

Congrats on all the progress. I appreciate the updates. Maybe shifting to relutrigine actually. You're pursuing this broader label, the EMERALD study for all DEEs. So how many different DEE patients in the Phase III does the FDA want to give you a broad label? And how many different DEEs have you enrolled so far? And secondly, for that study, as we think about what you want to see, is it fair that you might be expecting efficacy to be similar or even stronger than what you saw in SCN2A/8A and maybe explain why?

Yes. Thanks, Andrew. So, if you look into EMERALD right now, right, let me separate a couple of things there. So, one, as I mentioned in the remarks and then Tim mentioned as well in one of the answers, the goal here at this point in time is to get that sNDA by next year, right? And it should give you the confidence on what's happening on the study right now. Really incredible interest, incredible enthusiasm and engagement from the physicians that are referring to the sites or participating at sites in this study. We took a very basic approach, right? If you go and you look into the most recent definition of these, Dr. Scheffer recently published around this and really going back to the basics, right? What is the developmental epileptic encephalopathy, what are the drivers, like what should we be treated? And relutrigine sits like on that junction of really helping the broadest population, at least hypothetically right now since we're going to have to see the results in DEE. So we took the approach of phenotypically defined versus genotypically defined these patients for this study. What I can tell you right now without saying too much is that it is a very diverse group of patients that we have on the study, both enrolled studies and patients in screening, very diverse, not completely unexpected or unexpected at all. And when we position and we discuss this study with the agency, and I can never speak on their behalf, but I tell you our interpretation is that the idea here is to treat the disease, is not to treat the cause of the disease, would be pretentious to any of us to try to do that. And the understanding is that you cannot have a seizure without participation of sodium channel in the neurons. And therefore, this is like omnipresence type of mechanism that we can use. So that is the definition right now. There is no subgroups or there are no quotas for different, if I may, for different etiologies. So we're really looking into like an overall effect. When you go back to the last part of your question, and what to expect here. We need to go back to translation. We need to go back to the preclinical data since we do not have the clinical data yet. And when you go back there and we look into all different models and we tested all the fundamental electrophysiology and basic biology of this channel, deposition, the physical density of the channels in a critical juncture in the neurons, what we see is like quite overwhelming preclinical efficacy. So when we had that before on SCN2A, on the different models with SCN8A on the allogenic model, I think the way we're looking into that is like those are very good translational models. Now we have clinical data on those indications that translated well. So we expect to translate well as well. I think it would be a little bit too early to guide on how well the translation would be. But you've got to remember, from an overall DEE perspective, there is basically nothing for these patients as well. So while I'm incredibly excited about showing results maybe the same, maybe better than what we're seeing on 2A and 8A, it's absolutely not needed to deliver a very fundamental change on the way these patients are treated right now. But as I said in the past, we're going to see this soon enough. So we're just going to keep our heads down executing on EMERALDs, and soon enough, we're going to be discussing hopefully, significant benefit for patients on that population.

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

Marcio, maybe a little bit of a follow-up on that last question in terms of relutrigine and then I have a follow-up on vormatrigine. But just sort of when you anticipate utilization, do you see sort of utility across the -- it sounds like you see utility across the entire spectrum and even in indications where there are sort of ASOs or sort of more targeted therapies being developed and arguably sort of relutrigine will sort of become a workhorse used regardless of what other therapies may also be deployed for a particular patient populations.

Yes. No, that's a very good question, Doug. The workhorse, probably I wouldn't use that term, but I'm glad you did because I think that's one way to look into a drug like in a toolbox like relutrigine, where physicians would have that available that they don't have right now, right? They have to ask too many questions, too many trials. Like unfortunately, a lot of those patients don't have that time to keep trying and optimizing. And quite importantly, like there's, what, 20, 25 drugs that are normally tried in this population, virtually none of them have been tried and officially, like with randomized studies properly developed in pediatric populations or in adolescents or early adults here. So we never talk about that other side of label use that we really don't know what you're doing on those populations. So what we hear a lot from physicians here globally is that certainty of the drug that's being rationally developed for this indication. So there's a lot of enthusiasm there. Now to think that this is a silver bullet would be like completely absurd, right? There is not such a thing as a silver bullet in medicine. I think we all wish there was, but that isn't. So we do see this as a kind of an overall background therapy for some patients, ideally would be monotherapy. For other patients, they're going to continue in other drugs. You mentioned ASOs, particularly. I think ASOs are getting consolidated as kind of the second workhorse I think we're finally beyond some of the dreams we had about other modalities on gene therapy and really understanding that, that's a very, very good mechanism. So combinations between ASOs, for example, and others and relutrigine, we expect to be the norm. We look forward for the moments where these discussions are about how the use is happening versus all these hypotheticals because these patients don't have a lot of time and really excited about helping them.

Okay. Great, Marcio. That's really helpful. And then just on vormatrigine, I'm just curious, in the RADIANT study, as patients go sort of past the initial point and we're in the open-label extension, I'm just curious, have you gotten data or seeing data of patients who are withdrawing some of their background meds, sort of a little bit of a preview or look, if you will, into the POWER3 study, and in particular, patients who are maybe able to pull off sort of some of the more problematic -- sort of efficacious but perhaps more sort of less tolerable drugs like cenobamate or carbamazepine, et cetera?

Yes. We're seeing across the board reduction, elimination, removal of background therapies as patients continue to have experience on the open label vormatrigine. Physicians are very excited about the possibility, and I would say patients are more excited about that. As you can imagine, of course, efficacy is king here, right? But the queen is safety for these patients. And it is very hard for them to daily operate as humans when they are like on all those medications. So it's always very important. It's not only that, right? I think one of the drugs you just mentioned has just been like put on a new warning for drug-induced liver injury. So you got to think about the long-term impacts of these drugs and being vormatrigine at least so far, like so clean, it's quite important for these patients as well. So we're seeing more and more enthusiasm. Of course, every time you remove a drug, the first question you need to ask is what happens to the primary measure, what happens to seizures. And I'm very happy to preliminarily report they were seeing exactly what we were expecting to, it's maintenance of seizure control while really not being necessary to use. I believe you asked this from a clinical perspective, but I'm going to jump into here into the commercial perspective as we believe the value proposition of by the very first time on a drug that you can sequentially reduce the use of other drugs is very different than a drug that is just from the top, get used for a little bit and may be removed. So very excited. I think we're going to have more data and more discussions to talk about that when we have the POWER1 results as well and giving an overall program update.

Yes, yes, absolutely. So, maybe the easiest part of the question, you absolutely know where these patients are. I think we have daily motivation as patients keep calling our IR line, keep sending us messages and keep reminding us to keep pushing that they are waiting. It's quite motivating for me and for the rest of the team to keep moving there. And just like the millions of patients that we have mapped to prescribers in the U.S., that in a sense, I think it answers the second question or the first question that I'm answering second, while there is huge unmet need outside of the U.S., and we appreciate that, and we are very compassionate in relation to that, the focus of the company has to be in the U.S. right now. We were laser-focused on making sure the highest possible quality NDA was submitted. Now we are laser-focused at the highest possible quality launch is done for this. And when looking into the magnitude of this launch, I think you would be conceived and intended for us to get distracted at this point in time with other geographies. So very good trajectory, very good number of patients, as you can imagine, in open-label extension right now, which we would expect they would transition right away to commercial. other pools of patients that we believe are going to be right before and then just the spontaneous demands that we are seeing piling up on top of our database already for the launch. So I don't want to get over our skis here, but it is definitely trending towards a successful launch.

Our next question comes from the line of Ami Fadia with Needham & Company.

Congratulations on the submissions, both the submissions this month. My question is on vormatrigine and regarding how -- what you assumed for your peak revenue potential, particularly regarding utilization in first line and if you could provide some color on how you see utilization in earlier lines of therapy impacting persistency of patients and duration of treatment? And how will the POWER program help you build the clinical data that supports or provide some color on how long patients stay on treatment as they get treated with vormatrigine in earlier lines of therapy?

No. Thanks, Ami. So the retention we are seeing right now, right, as an early indicator of what you are asking, it's incredibly high. And once we talk about POWER1 results, we're going to be able to talk about that as well. Patients not only participating in these studies, but really staying on the long run. So that gives us an early flavor of how retention in overall commercial is going to be. And of course, they are staying on drug differently from other drugs and different from other trials because they are having a benefit and because they're having a safe experience with this drug. The way we currently forecast the movement between third line, second line, first line is actually very responsible, I would say. So we're not looking for this at day one of launch, we're not even looking to the year one at launch, we know it takes time for these things to happen. We know that the overall penetration is not like the highest. But when you look into our peak revenue right around $4 billion or so in overall, like you can imagine that we couldn't just be hyper penetrating the first line because otherwise, this would be much, much higher than what we have right now. So there is a huge potential there for upside, as you can imagine. But at the same time, as we -- there are many firsts that happened for us, right, in the last few years. And I think we're always very responsible to say what we knew and what we didn't. And I think what we know right now is that there's incredible interest on utilizing this drug. What we don't know is the dynamic of that. So we are really keeping, I would say, very tempered our enthusiasm in terms of how the penetration is going to be there, and that's reflected on our conservative to realistic one could call PIC revenue right now.

Our next question comes from the line of Brian Skorney with Baird.

I guess we'll get some guidance on NDA acceptance, but wanted to just get your preliminary thoughts on if the review division has given any indication on an advisory committee for either relutrigine or ulixa. I mean it seems that ADCOMS are getting more rare under this current iteration of the FDA. And relutrigine's mechanism seems pretty straightforward with the data. I probably wouldn't require one, but thoughts on ulixa in particular.

Yes. No indication whatsoever at this point in time. One wouldn't expect much of an indication before day 60 and day 74 interactions with the agency, but there is no indication right now, Brian.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on all the progress. As you plan your prelaunch activities for both ulixa and relutrigine, can you talk about the potential synergies you can leverage between these two launches? And then eventually, how those synergies could help set up your future launches of vormatrigine and elsunersen?

Certainly. So from a -- I'll take from the borrowing side, right? From an infrastructure perspective, back-office perspective, lots of synergy and how things are set up, and we've been doing a lot of that on the backgrounds, like how the systems are set up and so on. Until not that far in the past, we were actually considering a lot more synergy in the field as well and on the approach to the market because we believe before EMBOLD's positive results last year that would have a little bit more time with relutrigine, so we'll be able to leverage that. And that changed a lot once we are now really launching two drugs in about the same time. While there is a very significant overlap in I'm going to call

Our next question comes from the line of Kambiz Yazdi with BTIG.

Congrats on the NDA submissions. Three questions on my end. First, can you provide an update on the essential tremor patient database? How is that already validated the size of the ET market? Second, the FDA's default position is that one adequate and well-controlled study combined with confirmatory evidence will serve as the basis of marketing authorization of novel products. How do you think about that with regards to vormatrigine and FOS? And then my third and final question is, how should we think about the timing of relutrigine EMERALD top line? Would an interim analysis be a possibility for EMERALD?

Thanks, Kambiz. I try to go through your questions here if I understood them correctly, right? So on -- and I think I missed the very first one, so I might ask you to repeat which one was on ET.

Yes. The first one was, can you provide an update on your essential tremor patient database? How is that already validated in the size of the ET market?

Yes. So we'll continue to both validate and grow. And I think we intentionally didn't talk about this today since now we are moving from the clinical focus one to the commercial focus effort, and we're going to give like a larger update at our Commercial Day in the near future there. So I'm going to keep you holding your breath a little bit in relation to that. I'm going to go to the EMERALD and then go back to the second question. So, of course, there's always an opportunity for In-Trem. It's not a current plan for EMERALDs. And the reason why it's not a current plan is really the pace of enrollment in EMERALD right now. I think we've been realistic/conservative about the time lines today, but that is really a very fast pace of enrollment that might not allow for that. And then on the last one and how we think about generation effects vis-a-vis the Commissioner like New England Journal of Medicine yesterday publication, we applaud it. I think it can be and will be -- I have but trust on our country that's going to be used responsibly. And we believe that in drugs where very clearly like epilepsy, very clearly, the second study was not necessary in the best. Those are good case studies and tests for the future. We could not possibly be trying to guide you today that, that's going to be the standard for our drugs. There's a lot of water that needs to go under that bridge, but we are enthusiastic about what that can do for drug development and for Praxis, particularly in the near future. So stay tuned.

Our next question comes from the line of Justin Walsh with JonesTrading.

With your clinical successes, have you been seeing increased attention paid to your Cerebrum platform? And related to that, can you remind us how both Cerebrum and Solidus are differentiated in their ability to select quality candidates for your pipeline?

Yes, yes, absolutely. We do. As you can imagine, that is I think just in like a renaissance, maybe I would say, on understanding that the best mechanism to address a lot of this disease is through antisense oligonucleotides. So we're seeing a lot of interest across the board actually on this. You're going to hear more in the near future about how we're going to maximize. I also believe that there's a different way. We talked about standards today. I talked about plausible mechanism today. There are different things there to maximize. We always follow two pillars, right, the biology, and what is the best way to address and then the business on the other side. Without business, biology is irrelevant. Without biology, business is irrelevant. So I think we try to do both of them, and that's why we're here today discussing the successes and the future success. So I think that is -- stay tuned, but there's going to be a lot more on that platform as well.

Our next question comes from the line of David Hoang with Deutsche Bank.

So maybe first one on ulixacaltamide in essential tremor. Could you just discuss a little bit about the distribution of the prescriber base? How well do you understand whether these prescribers will be based in, let's say, academic centers versus community, this is a product that would be prescribed by general neurologists broadly? And then one on vormatrigine. As we think about the evolving landscape in focal epilepsy, there's several potassium channel focused therapies that are in late-stage development and potentially coming to market soon. How do you think vormatrigine fits in amongst those products? And what would docs look at when selecting a therapy?

Thanks, Dave. The distribution, and I would say the distribution of patients and the distribution of drug and the prescribing pattern is very well understood. I think we've been talking about that for a bit. It was one of the very first functions and knowledge that we built in the company. I would arrogantly tell you that we have an exquisite understanding on this. And each one of the physicians that have case in the U.S. right now is the majority of them, the vast majority, general neurologists, and they're very eager and willing to engage with us. I think on pharma and the competitive landscape, this was not and never going to be a zero-sum game. We welcome. We are cheering for the next readouts on this space coming up soon. And we believe that, that is really -- is in the best interest of patients that there are multiple positive readouts and drugs, and we can use them. And we just see the path to first line only happens with vormatrigine. So competitively, welcome going to have some competition on the refractory patients on the third line, but there's no competition on the earlier lines. Thanks for your question.

Our next question comes from the line of Ben Burnett with Wells Fargo.

I want to come back to an earlier question on ulixacaltamide and just the potential to explore titrating patients. I think you mentioned an alternative titration protocol. I guess curious if you could give us a little more color on this. And I guess, would this alternative titration protocol start patients at a lower dose? And then secondly, you also talked about standard review for ulixacaltamide, and I think you walked through a couple of sort of business reasons for that. But it feels like it also would give you some time to maybe iron out a titration protocol. And was that also a consideration?

Yes. Thanks, Ben. The -- no, there was not a consideration. Actually, I'll say there was not an important consideration. Of course, it's always up to the FDA if they want to discuss more. We had a very robust discussion about that topic with the agency before it was very good to see that this is not a major concern, but there's obviously an interest from us and from them when there is an efficacious drug that we try to actually expose and get the maximum amount of patients. That is the idea. It is not a lower dose, right, starting at 20 milligrams. It's just staying at 20 milligrams for longer because what we see here is what looks like it's really just a few days that they stay longer on that dose that tends to subside the side effects and then they have the opportunity to have the effect. So that's the idea there. I think, of course, there's thousands of things that can come up in conversations with the agency, but that was not one of them that we are planning as a main conversation for sure.

I would now like to turn the call back over to Marcio De'Souza for closing remarks.

Yes. Thank you, everyone. I think we run a little bit even over the allotted time. So I appreciate you all hanging in with us here, the enthusiasm shared by all the analysts and our shareholders. I can't say how much I appreciate and all of us here at Praxis appreciate the patients that participate in all these studies that continue to engage with us as we are here very humbly submitting NDAs, which I don't believe has ever been done by a company in our stage on the same quarter. The real motivation for everyone that worked like days and nights on the last several years, but particularly in the last few months has been the fact that there is someone, as we say, outside of the door that we don't know they need these drugs. So just going to dedicate this moment to all of them and thank them for participating in our studies. I looking forward to interact with all of you soon, and thanks for tuning in.