Praxis Precision Medicines, Inc. Q4 FY2025 Earnings Call

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2025 Earnings Call. 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 timelines, and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking 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 by the breadth of significant clinical achievements and regulatory advances across our portfolio with positive readouts and FDA interactions for ulixacaltamide, relutrigine, and vormatrigine, as well as an 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 basis for 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 ulixacaltamide showing meaningful improvements in the mADL11 in the rate of disease progress, PGI, and CGI. Study 2 also met its prespecified primary endpoint with ulixacaltamide demonstrating a superior maintenance of effects during the randomized withdrawal phase. This was the first time an investigational therapy designed specifically for patients with essential tremor 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 been 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 approval in the near future, our preparations for the commercial launch of 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 in immediate need for therapy or an addressable population, as we call it. 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 about 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, and the opportunity for responsible pricing that recognizes the value of the drug, we have been building our commercial organization infrastructure, including key hires and core aspects of the pre-launch 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 will 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 sharing 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 continued to deepen with time. Given the strong efficacy results and the favorable safety profile, underscoring relutrigine's 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 the DEE space could be as large as $5 billion in annual revenue. Similarly to the efforts for ulixacaltamide in essential tremor, we have initiated pre-launch activities for relutrigine, including key hires and building sufficient inventory for a successful expected launch. 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-daily 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 a 50% reduction in seizures at week 1 without the need for titration. This effect continues to increase, with patients who proceeded to the OLE achieving a 100% median weekly seizure reduction at week 9, which was sustained through week 16. Additionally, we saw that 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, with the 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 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 is 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 the 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 the full year were driven by 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 in 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.

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

Our first question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on 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. 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 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 ensuring a smooth review with the agency. And on the other side of that, the prescribers really understand or potential prescribers really understand the disease on one hand, which they understand well, but there's obviously a good reminder there. And on the other hand, the clinical data for ulixacaltamide 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. Several 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 is, 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 in the overall community of this very strong clinical data set. So we're going to be discussing 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. Throughout the presentations, there are very robust and 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 I'm incredibly excited and very grateful to the scientific community of AAN for 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 ulixacaltamide. 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. Maybe I'll break it down, if I may, your questions into two parts, right? So we've been discussing since you asked about education. 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 easy-to-manage 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 submitted the proposed label to the FDA, not only the standard titration that was done in the clinical study, right? So seven days at 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 that must prevail in terms of what the final label is going to be. So it would be pretentious for 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 pre-approval on this regard. So we always respect the opinion of the FDA and the guidance they give; of course, without this requirement, I believe — and now that's my interpretation — that is because this is really not a safety issue, right? There 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 look at it from a benefit-risk perspective, it's very well balanced. We're going to see how this progresses during the review, and we're very enthusiastic about the possibility of serving not only the 70% 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 preparation for both relutrigine and ulixacaltamide, how much capital allocation should we be thinking about between the two programs?

I think in terms of allocation, you can imagine that with ulixacaltamide being a much broader market, we will probably be 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. 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 populations, 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 timeline. So we — I think, Marcio, it would be good if you can address the review timeline 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? Just a reminder of what we are trying to accomplish here. POWER1 is like the first study here for 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 happy with how enthusiastic the investigators were in enrolling patients in this study, particularly considering competitively how well this study enrolls. POWER2, as we're enrolling quite nicely right now as well, would be the second registrational. When you look into the market, I would say a part of this market that is the more refractory patients or even hyper-refractory patients treated multiple ASMs are really struggling for years and years, possibly decades here. Most drug development and the focus from Level 4 epilepsy centers and key opinion leaders have been on these patients. However, when you consider the rest of the market, it's probably unfair to call it the rest since it's the majority of the market. These are the patients that have 70%, 80% of focal onset seizures; they still can strive while suffering from breakthrough seizures from time to time. They are not doing well, and the market has remained untapped until now. Speaking with those physicians who treat a significant number of patients, they express a need for a drug that they can trust and feel confident in, and they are very enthusiastic about vormatrigine for that matter. So we’ve been in consultation with them, finalizing the design, and we are going to be discussing this throughout the upcoming periods. What it does for our drug, while not required for registration, is very exciting. We are just in a privileged position that vormatrigine might be the drug that allows patients and physicians to have confidence in treatment. Regarding the review timelines, you can imagine that decisions we have to make are multifold. The timing of the submission is now in the past. The second is the entire understanding and relationship with the agency; this is critical. DN1 or Division of Neurology I and II are two different divisions, and there’s a lot of shared resource. We’re having two NDAs at the same time with them. Very obviously, relutrigine will be easier. It’s not because it’s easier from a clinical perspective but from a workload perspective, as it has much less data being a single study for a rare indication. We decided to request a priority review for that application, but we decided not to request for ulixacaltamide for multiple reasons. Those that I just mentioned, but there’s a broader business reason about the time of the launch and the maximization of revenues over time for this drug, particularly around payer dynamics that happen later in the launch. On a drug that can and will be as big as ulixacaltamide, we cannot just focus on the dollars and forget about the potential millions, so we need to be very strategic 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 the 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 ulixacaltamide in ET. And the last question is, in the past, you telegraphed around a $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 in terms of forecasting this drug. Of course, there are multiple dynamics, and you just named some of them, like what payers and reauthorization and potential step edits— you name it—but the Inflation Reduction Act and the dynamics of the Act right now is an important consideration as always. This is a heavily Medicare Part D population. So we want to ensure we're responsible for how we're launching while maximizing and providing proper value for the drug. This includes considering the life cycle of the evolution of the current iteration of the act, when it impacts, when it kicks in. I believe that's where you are going there. There’s a significant difference in value depending on when that negotiation happens, and it was a key consideration in our filing strategy. Regarding the data to be presented, yes, we will always present more and more data to reinforce both the short-term and long-term value of ulixacaltamide in essential tremor. One point we believe there's still room to explore is really how strong the data is. I know you recently spoke to some payers and payer groups, and if I understand correctly, they agree with the strength of the data and the high potential for this drug. However, the understanding is not yet clear in the market, because we haven't disseminated the data showing how deep the effect is across a large proportion of patients. When looking into drugs, it's not one size fits all. So we want to ensure that the evidence gets reinforced and fully reviewed holistically.

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. If you look into EMERALD right now, let me separate a couple of things there. One, as I mentioned in the remarks and Tim mentioned as well in one of the answers, the goal here is to get that sNDA by next year, right? And it should give you the confidence on what's happening in the study right now. Incredible interest, 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. If you look into the most recent definition, Dr. Scheffer recently published around DEEs, we went back to the basics—what is the developmental epileptic encephalopathy; what are the drivers, and what should we treat? Relutrigine sits at the junction of really helping the broadest population, at least hypothetically, since we're still waiting for results in DEE. We took the approach of phenotypically defining versus genotypically defining 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 enrolled in the study, both currently in studies and patients in screening. When we discuss this study with the agency, while I cannot speak on their behalf, I can tell you our interpretation is that we aim to treat the disease and not the cause of the disease. The understanding is that you cannot have a seizure without the participation of sodium channels in the neurons. Therefore, this is an omnipresent mechanism we can utilize. There are no subgroups or quotas for different etiologies, so we are looking for an overall effect. Regarding what to expect, we seek to return to translation. When we look at all the different models, we tested fundamental electrophysiology and the basic biology of this channel, the density of the channels in critical junctures in the neurons demonstrates quite overwhelming preclinical efficacy. We previously observed for SCN2A, as well as other recognized models. We expect to have a strong translation as well. I think it would be early to guide on how well the translation would be. As I said in the past, we're going to see this soon enough, so we just keep our heads down executing on EMERALD, and soon we will hopefully be discussing significant benefits for patients in 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. I have a follow-up on vormatrigine. But just sort of when you anticipate utilization, do you see utility across the whole spectrum? It sounds like you see utility across the entire spectrum and even in indications where there are sort of ASOs or more targeted therapies being developed. Arguably, relutrigine will become a workhorse used regardless of what other therapies may also be deployed for a particular patient population.

Yes. That's a very good question, Doug. The notion of a workhorse, I wouldn't use that term, but I’m glad you did because that is one way to look at relutrigine in a toolbox where physicians would have it available—this is exactly what they do not have right now. They currently are trying to ask too many questions, trailing too many trials. Unfortunately, many of these patients don’t have the time to keep trying and optimizing. Furthermore, there are what, 20 to 25 drugs that are often tried in this patient population; almost none have been evaluated in randomized studies in pediatric populations or early adults. The however is that there is so much excitement from global physicians about this drug rationally developed for this indication, and there’s enthusiasm there. To think this will be a silver bullet would be absolutely absurd; there is such a thing in medicine. While we anticipate this drug could ideally serve as monotherapy, we also foresee patients continuing on other therapies. You mentioned ASOs, which we expect to act as the second workhorse; we are finally beyond some of the aspirations we had for other modalities in gene therapy. We expect combinations of ASOs and relutrigine to be the norm as we shift toward discussions on utilization and not just hypothetical scenarios, since these patients don't have much time.

Okay. Great, Marcio. That's really helpful. And then just on vormatrigine, I'm just curious; in the RADIANT study, as patients progress past the initial milestones and into the open-label extension, have you been able to observe any data of patients withdrawing from background medications? Specifically, I’m interested in some of the more problematic, albeit efficacious, drugs like cenobamate or carbamazepine, etc.

Yes. We’re seeing across the board reductions and eliminations of background therapies as patients continue to experience the open label with vormatrigine. Physicians are very excited about the possibility, and I would say patients are more excited. As you can imagine, of course, efficacy is fundamental, but safety is also paramount for these patients. It’s very challenging for them to operate daily while taking multiple medications. Each time a drug is removed, the first question is what happens to the primary measure—what happens to seizures. I am very pleased to preliminarily report that we see what we expected; this results in the maintenance of seizure control while removing unnecessary medication. I believe you asked this from a clinical perspective, but I want to mention a commercial perspective, as sequentially reducing other drugs from potential treatments presents a very different value proposition than a drug that just gets used initially and may be removed later. So we’re very excited; we expect to gather more data and insights when we report the POWER1 results and provide an overall program update.

Our next question comes from the line of François Brisebois with LifeSci Capital.

Congrats on all the progress. It's quite a year for you guys. Maybe on elsunersen, there's a lot to touch on, but I don't think much has been discussed on this one. Can you help us—EMBRAVE data is coming soon. So just maybe set expectations there a little bit. And I think there's so much going on with the company that maybe help us understand why it's so important to have an update on just having a single-arm comparison for EMBRAVE3 and what that means.

Yes. So, thanks for that, Francois. The elsunersen slide, as we call it, indeed sometimes takes a backseat. I appreciate the link back to your earlier questions about the ecosystem—these drugs will all be used; they will have different case use scenarios, one more, another less or in combinations. Right now we have a cohort of nine patients, randomized 3:1 to sham or drug. Our intention there was to continue to understand the safety, efficacy, and PK of this drug. We’re optimistic, as we have control data that can independently and even open-label data leading to independent conclusions about these nine patients’ responses, creating another opportunity for us to understand the drug impact. We know the study went exceptionally well with these patients from a safety monitoring perspective, which isn’t a given. We believe this can yield very valuable insights while being respectful of the program's overall scope. The FDA was very encouraging about pursuing EMBRAVE3 as controlled on baseline because they are eager to accelerate drug development for medications with high potential translatability, and this drug fits that description. We did switch what was to be a double-blind sham control study into a single-arm, and the experience with all investigators and patients globally has been very positive. While longer timelines are anticipated for this study, we expect to complete it this year, which may support another NDA application.

That’s very helpful. And then on ulixacaltamide, I don't think you mentioned anything about ex-U.S. efforts. I was just wondering, such a big market here; I assume ET is a global phenomenon. Any thoughts on that you can share? And then the launch, obviously without priority review; this may be a little premature, but you've had so many trials and so many patients on this. I'm just wondering in terms of line of sight on launch trajectory from the outset; do we know where these patients are? Any color there would be helpful.

Yes, absolutely. The easiest part of your question is that we know exactly where these patients are. I think we draw daily motivation from patients who continue to call our IR line, message us, and remind us to keep pushing for their need. It is motivating for me and the whole team to keep moving. Just like the millions of patients we've mapped to prescribers in the U.S., this answers your second question, where there is huge unmet need outside of the U.S. We understand and appreciate the situation, but the company must focus on the U.S. right now. We are laser-focused on ensuring the highest quality NDA for submission, and we are also laser-focused on making sure the highest quality launch is executed. Looking into the magnitude of this launch, we would be remiss to allow ourselves to become distracted from focusing on other geographies. We have a promising trajectory and a significant patient base, while open-label extension results indicate we expect patient transition success to commercial. We also see a growing demand piling up on top of our database already as we prepare for launch, so I don't want to get ahead of ourselves as we build towards what looks to be a successful launch.

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

Congratulations on the submissions, both submissions this month. My question is on vormatrigine and regarding how you plan to account for peak revenue potential, particularly regarding utilization in first-line settings, if you could provide some color about how you see utilization in earlier lines of therapy impacting persistency of patients and the duration of treatment. And ultimately, how the POWER program will aid in providing clinical data on how long patients stay on treatment as they are treated with vormatrigine over earlier lines of therapy?

The retention we are seeing right now is incredibly high. Once we discuss the POWER1 results, we will be able to elaborate more on that. Patients participating in these studies are staying in the long run, which gives us an early indication of what patient retention will look like in the overall commercial context. They are remaining on the drug longer than others because they are experiencing positive benefits and safety from the drug. Our current forecasts for the distribution between third line, second line, and first line therapy is realistic. We are not planning to have this happen on day one or even year one; we know it takes time. Hence, while our peak revenue forecasts are around $4 billion, we could hardly project hyper penetration in the first line as that would project higher revenue potential. We have excellent potential here for upside as well but will prudently recollect from our experiences over the last few years and offer realistic forecasts for penetration at launch.

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

I guess we'll get some guidance on NDA acceptance, but I wanted to just get your preliminary thoughts on whether the review division has given any indication on an advisory committee for either relutrigine or ulixacaltamide. It seems that ADCOMS are getting more rare under this current iteration of the FDA. Relutrigine's mechanism seems pretty straightforward with the data; I probably wouldn't require one. But thoughts on ulixacaltamide 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 ulixacaltamide and relutrigine, can you talk about the potential synergies you can leverage between these two launches? Eventually, how those synergies could help set up your future launches of vormatrigine and elsunersen?

Certainly. From a borrowing side, right, a lot of synergy exists in the infrastructure and back-office aspects, and we've been working extensively on that. Until not far in the past, we were considering significant synergy in the field as well, but we realized that as we are actually launching two drugs around the same time, it’s prudent to take dedicated go-to-market strategies for each of them individually. While there is significant overlap in terms of ‘ZIP codes’—hospitals and clinics with high overlap of patients with both essential tremor and DEEs—we will be maximizing these efforts separately in the short term. Now when you consider the long-term potential with focal seizures, generalized seizures, and other indications that may arise in the future, we see very high overlap between prescribers in most epilepsy patients today and most essential tremor patients. You can visualize how Praxis’ presence can be powerful in that regard in a few years. That said, we have over 70% of prescribers for ET and focal epilepsy present at the upcoming AAN meeting, which will provide a fantastic opportunity to demonstrate synergies over time.

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 has 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 for the 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 possible for EMERALD?

Thanks, Kambiz. I try to go through your questions here if I understood them correctly. The first question was about essential tremor. Yes, the database will continue to both validate and grow; however, we intentionally did not discuss this today since we are transitioning from a clinical to a commercial focus, and we will provide a more substantial update during our Commercial Day soon. Regarding EMERALD and whether an interim analysis is planned, it’s not our current plan to use an interim analysis due to the pace of enrollment currently seen, which has rapidly exceeded expectations. Finally, on the standard for marketing authorization and associated studies—what we're seeing and encouraging trends—with very importantly, the recent NEJM publication that will be a benchmark for future FDA interactions; we're optimistic about seeing responsible approaches within the review, allowing us to pursue trials necessary to deliver the most effective treatments more rapidly.

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, absolutely. We do see increased interest, given the renaissance on understanding the best mechanisms to address these diseases, especially through antisense oligonucleotides. We're going to see a lot on this in the near future. As you know, we track two primary pillars: biology— the best mechanism to address and business. Without solid business fundamentals, biology fails, and vice versa. Therefore, we work across both tracks, which is why we stand here today discussing current and future successes across the company.

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

So maybe first 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; is this 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 are 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? What would docs look at when selecting a therapy?

Thanks, Dave. The distribution of patients and prescribing patterns is indeed well understood. I would say we have a clear and nuanced understanding of this market, primarily consisting of general neurologists eager to engage with us. I think the competitive landscape presents an opportunity rather than a threat: we welcome and cheer for the next developments in this area. We believe it's in the best interest of patients to have numerous effective treatments become available—in light of this, we see a pathway to first-line use for vormatrigine in particular. There is competitive momentum for refractory patients, especially in the third line, but no competition in earlier lines. Regarding how vormatrigine fits into the landscape, we are optimistic and see it as benefiting from seen competitive advantages in safely treating patients who have suffered through many unsuccessful treatments.

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 I'm curious if you could give us a little more color on this. Would this alternative titration protocol start patients at a lower dose? And secondly, you 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. Was that also a consideration?

Yes, thanks, Ben. There was no consideration towards using standard review to buy time for the titration protocol; however, it is a topic we discuss with the agency. The alternative titration protocol is not about starting at a lower dose, but rather remaining longer at the 20mg dose. This approach helps patients better manage tolerability while promoting the effect. We do not expect the FDA to explore pre-approval clinical studies on this matter since it's not a safety issue; rather, it's about managing tolerability, which could be beneficial. Thank you, everyone. I think we run a bit over the allotted time. I appreciate you all hanging in with us here and your 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 at our stage in the same quarter. The real motivation for everyone that worked days and nights over the last several years, but particularly in the last few months, has been the fact that there are patients outside this door that we don't know who need these drugs. So I just want to dedicate this moment to all of them and thank them for participating in our studies. I look forward to interacting with all of you soon, and thanks for tuning in.

This concludes today's conference. Thank you for your participation. You may now disconnect.