Praxis (PRAX) Q1 2026 Earnings Call Transcript

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Date

Thursday, May 7, 2026 at 8:30 a.m. ET

Call participants

• Chief Executive Officer — Marcio Souza
• Chief Financial Officer — Tim Kelly

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Takeaways

• NDA status -- The NDAs for ulixacaltamide and relutrigine have been accepted by the FDA, with PDUFA dates set for Jan. 29, 2027 and Sept. 27, 2026, respectively.
• Ulixacaltamide commercialization -- The company is preparing for a U.S. commercial launch based on the Jan. 29, 2027 PDUFA date, with a commercial leadership team and field force in place, and distribution networks and infrastructure established across operations, marketing, access, and compliance.
• Ulixacaltamide market opportunity -- Management estimates over $10 billion in peak sales potential for ulixacaltamide, targeting approximately 2 million of 7 million essential tremor patients deemed in immediate need of therapy.
• Physician and patient research -- More than 2,300 U.S. physicians and over 1,300 essential tremor patients surveyed validated ulixacaltamide's efficacy, breadth of benefit, and tolerability profile.
• Relutrigine NDA -- The FDA granted priority review for relutrigine for seizures associated with SCN2A and SCN8A-DEE, with a PDUFA date of Sept. 27, 2026 and potential eligibility for a pediatric review voucher upon approval.
• DEE market potential -- The broad DEE patient population in the U.S. exceeds 200,000, offering significant expansion opportunity for relutrigine beyond the initial SCN2A and SCN8A indication.
• EMBOLD study recruitment -- Recruitment for the EMBOLD study in the broad DEE population is complete, with top-line results expected in Q4 2026 and the possibility to support a supplemental NDA submission in 2027.
• POWER1 and POWER2 milestones -- The POWER1 study readout for vormatrigine is scheduled for later in Q2 2026, and enrollment for POWER2 is on track to complete by year-end 2026, with data expected early 2027.
• Elsunersen clinical data -- In the EMBRAVE Part A study for SCN2A early-onset DEE, elsunersen achieved a 77% placebo-adjusted reduction in monthly seizures, maintained a generally safe and well-tolerated profile, and demonstrated disease-modifying effects across multiple domains.
• Operating expenses -- Fiscal Q1 2026 operating expenses were approximately $106 million, including $78 million for R&D and $28 million for SG&A, reflecting increased clinical activity and commercial preparations.
• Cash burn -- The company used $86 million in operating cash in fiscal Q1 2026, up from $53 million in fiscal Q1 2025, driven by higher clinical trial activity, headcount growth, and launch readiness.
• Cash position -- As of March 31, 2026, the company reported $1.4 billion in cash, cash equivalents, and marketable securities, primarily due to a January 2026 follow-on public offering and interest income, offset by operating cash use.
• Runway -- Management states the current cash position is expected to fund operations into 2028.
• Manufacturing and supply chain -- The company has secured two independent drug substance manufacturers for ulixacaltamide and is building sufficient inventory for both ulixacaltamide and relutrigine, with different distribution strategies tailored to each product.
• Disease state campaign -- The "Essential2 Me" campaign launched in April 2026 to drive physician engagement and expand the prelaunch database of providers and patients, receiving "fantastic" early response.
• Compliance and retention insights -- Physician advisors in the company's observational studies expressed comfort with managing ulixacaltamide's initial tolerability profile, with management noting, "the single most important driver of retention of patients in the long run."
• Dose flexibility strategy -- For vormatrigine, management intends to bring 20-, 30-, and 40-milligram doses to market to maximize physician flexibility and address the heterogeneity of the epilepsy patient population.
• Sales and launch readiness -- Commercial hiring, field force build-out, and patient support programs are underway for imminent launches, with active engagement on payer discussions and pricing strategies.
• Portfolio breadth -- Management highlighted four late-stage assets, each positioned for value inflection and major clinical or regulatory catalysts in the next 12 months.

Summary

Praxis Precision Medicines (NASDAQ:PRAX) reported the acceptance of NDAs for both ulixacaltamide and relutrigine by the FDA, establishing clear timelines for two potential first-in-class U.S. launches within the next eight months. Ulixacaltamide's commercial launch is fully resourced and supported by data from large-scale physician and patient studies, while relutrigine's priority review status and anticipated broad DEE label could expand its reach to an estimated 200,000 patients. EMBOLD study enrollment closed rapidly, with top-line results targeted for late 2026, and POWER1 and POWER2 will generate critical Phase III epilepsy data in the near term. Elsunersen demonstrated a 77% placebo-adjusted seizure reduction in early-onset SCN2A DEE, providing the first clinical evidence of durable, disease-modifying potential in this indication. The company's substantial cash reserves, driven by a $474 million increase in fiscal Q1 2026, extend operational runway into 2028 and position the company to support multiple launches and late-phase readouts through a period of high strategic activity.

• The proportion of fiscal Q1 2026 operating expenses allocated to R&D (approximately 73.6%) versus SG&A reflects heavy investment in moving multiple programs toward commercialization.
• Management described physician and regulatory engagement cycles with the FDA as offering "very good visibility" on key process steps for both late-stage NDAs.
• Marcio Souza confirmed that the EMBOLD study achieved fast enrollment by leveraging high-volume sites and ensuring "highest quality, first and foremost" standards throughout the process.
• The company has presented 15 scientific communications, including plenary sessions and award-winning abstracts, at recent neurology conferences, highlighting scientific credibility and strong clinical interest in its programs.
• The company plans to announce two additional indications for ulixacaltamide beyond essential tremor, with further details awaiting internal review and public disclosure strategy.
• Monotherapy studies for vormatrigine (POWER3) are in planning, with management stating, "others are not doing it because they cannot," reflecting unique product confidence.
• Commercial and manufacturing preparations include the ability to meet potential upside from larger-than-expected physician demand.

Industry glossary

• PDUFA date: The target action date set by the FDA under the Prescription Drug User Fee Act for completing the review of a new drug application.
• DEE (Developmental and Epileptic Encephalopathy): A group of rare epilepsy syndromes characterized by early-onset, intractable seizures and developmental impairment.
• ASO (Antisense Oligonucleotide): Synthetic strands of nucleic acids designed to modulate expression of specific genes, used as therapeutic agents in genetic diseases.
• Plenary presentation: A high-profile scientific presentation delivered to the entire audience of a professional conference, often awarded for major or groundbreaking studies.

Full Conference Call Transcript

Marcio Souza: Thank you, Dan, and good morning, everyone, and thanks for joining Praxis' First Quarter 2026 Conference Call. Building on a remarkable 2025, we have continued executing across our portfolio in our journey to become a commercial company with strong momentum building across 4 late-stage assets, representing more than $20 billion in peak sales potential. With the NDAs for ulixacaltamide and relutrigine accepted by the FDA and PDUFA date set, we're ramping up commercial efforts to support the 2 potential U.S. launches within the next 8 months while also making significant progress with our other clinical programs.

It's also incredibly exciting to announce that we have completed recruitment for the EMBOLD study in the broad DEE population, with top-line results expected in the fourth quarter of this year, which we expect to support a potential supplemental NDA next year. We're also on track to report results from our POWER1 study for lamotrigine later this quarter. Also made exciting progress with our solids ASO platform with the positive results from the EMBRAVE Part A showing a disease-modifying effect of easinersen in SCN2A early onset DEE and substantial reduction in monthly seizures, amongst many other results.

With key hires made in our commercial organization and a strong financial foundation, we're accelerating the delivery of life-altering treatments to patients with CNS disorders. Let me provide a bit more detail on each one of our programs. Let's start with Ulixa. FDA acceptance for Ulixa's NDA marks a meaningful step forward for the 7 million Americans living with essential tremor who currently have no ET-specifically developed treatments approved. We estimate that about 2 million of those people living with ET are in immediate need of a therapy that can clinically improve their daily lives, representing a potential for over $10 billion in peak sales.

To unlock the benefit for patients and the value, we have been diligently preparing for our commercial launch based on the PDUFA date of January 29 next year. The commercial leadership team is in place with our field force plan to be hired and trained in advance of the launch, and we continue to expand and build the commercial infrastructure across multiple areas, like operations, marketing, access, and compliance. We have also successfully established a distribution network to ensure drug availability at launch at successful levels. Earlier this year, we conducted a very comprehensive observational study with physicians to understand their view of ET and ulixacaltamide.

We surveyed more than 2,300 U.S. physicians who collectively manage tens of thousands of patients. The results were beyond encouraging. They validated the ulixacaltamide profile across efficacy, the breadth of benefits, and tolerability, reinforcing the more than $10 billion peak sales potential and the need for a drug like Ulixa in the market. Importantly, we also wanted to hear more details from patients and conduct a similar work with over 1,300 ET patients, which further validated the agreement between the needs of patients in terms of their functional benefits and the results of the Essential3 program. It's truly exciting to be in a place of such alignment amongst treating physicians, patients, and the results of our program.

We're also very pleased with our robust presence at the American Academy of Neurology Annual Meeting last month. With 15 scientific presentations, including a plenary presentation highlighting the Essential3 program results, which received the AAN's abstract of Distinction and Movement Disorder Awards, which underscore the strong interest and engagement of the medical community. To further enhance our engagement with health care professionals, we have launched the Essential2 Me disease state campaign. Let's now move to our epilepsy programs. As we shared in March, in another pivotal moment for practice and patients, the FDA has accepted with priority review the NDA for relutrigine for seizures associated with SCN2A &8A-DEE.

Those are severe patients affected early in life, and where the seizures are intractable from the very beginning. It's important to highlight that if approved, relutrigine would be eligible for a pediatric review voucher. With the PDUFA date of September 27, preparation for launch is moving full steam ahead with continued hiring of commercial roles, building sufficient inventory, establishing a comprehensive patient support program, and engaging with payers to ensure timely access upon potential approval. We remain confident in the clinical potential for relutrigine and the benefits to the broader DEE population. With recruitment in the EMBOLD study now completed in record time, it's clear that patients and investigators share our view.

The potential launch in SCN2A &8A will build the foundation and the results of the EMBOLD later this year; if positive, it will significantly expand the commercial potential for relutrigine by several folds, considering the broad DEE population is comprised of over 200,000 patients in the United States. Let's now talk about vormatrigine, the most potent and selective sodium channel modulator ever developed for the 3.5 million people living with epilepsy in the United States. We have 3 key milestones in the near future for the program. The first is the readout of the 401 Phase III study later this quarter.

Then the initiation of the POWER3 study, a milestone in the community, using all the exciting features of vormatrigine to deliver on what the majority of the market really needs. And then later in the year, the completion of the POWER2 Phase III study, which is evaluating doses of 20, 30, and 40 milligrams once daily. Enrollment is progressing well, and we're on track to finalize the study this year and report early next year. Lastly, let's talk about Elsunersen, the first ASO on our platform. also has a rare pediatric drug designation and is being developed for the treatment of early seizure onset patients with SCN2A mutations.

We have recently reported the results of EMBRAVE Part A, which enrolled 9 children aged 2 to 12 who were randomized 3:1 to elsunersen or sham over 24 weeks. We are thrilled with the impressive 77% placebo-adjusted reduction in monthly seizures and the disease-modifying components seen across multiple domains in those patients, while maintaining the generally safe and well-tolerated profile. The overall data from both the EMBRAVE program, open-label extension, and emergency use program globally highlight durable seizure reduction and meaningful global gains, which further underscore the transformational potential of this drug.

In conclusion, we're off to a great start with our momentum continuing to accelerate across our clinical portfolio, preparations for the commercial launch of ulixacaltamide and lamotrigine well underway, the completion of the EMERALD study enrollment, POWER1 top-line readout coming up, and many other achievements to come. Backed by a strong balance sheet and a long, multilayer IP portfolio across the programs, we're focused on rigorous execution and driving progress across our innovative first and best-in-class portfolio of CNS therapies. I'll now hand over the call to our CFO, Tim Kelly. Tim?

Tim Kelly: Thank you, Marcio. Good morning, everybody, and thank you for joining today's call. I'll provide a quick summary of our first quarter financials. In Q1, our operating expenses were approximately $106 million, with $78 million of that for R&D and the remaining $28 million for SG&A, driven by ramping activities and hiring related to commercial launch preparations. During the first quarter, Praxis spent $86 million in operating cash compared to $53 million in the first quarter of 2025, reflecting greater clinical trial activity, headcount growth, and commercial launch preparations. As of March 31, 2026, Praxis had $1.4 billion in cash, cash equivalents, and marketable securities compared to $926 million as of December 31, 2025.

This increase of approximately $474 million was primarily attributable to net proceeds from Praxis's January 2026 follow-on public offering and interest income on marketable securities, partially offset by the previously mentioned cash used in operations. The company's cash, cash equivalents, and marketable securities as of March 31, 2026, are expected to fund operations into 2028. With that, I will hand the call back to Marcio.

Marcio Souza: Thank you, Tim. I appreciate the review. We're going to move now to Q&A. Howard, maybe you can provide the queue for us.

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

Yasmeen Rahimi: Maybe also congrats on EMBOLD bringing to the finish line enrollment and data in 4Q as it's an important readout this year. Maybe remind us, what is the data that we have to support relutrigine working in a broader DEE population, both across preclinical and clinical data? And then also, what do you see on a blinded basis across safety and efficacy that continues to give you confidence in the high success in the EMBOLD study? And I'll jump back in the queue.

Marcio Souza: Thanks, Yas. I'll take a step back here and maybe talk a little bit about the genesis of going to the broad DE population. When you look into seizure activities, particularly on those intractable conditions like DEEs, we know full well just how difficult those patients are to control. I know that when they can have at least some partial control for the most part, it is because that is a way to inhibit the block, better modulate their sodium channel activity, like you simply cannot have seizure activity without participation of those channels.

So when we were conducting the EMBOLD program for SCN8A, the #1 question we're getting from physicians back then was, " When are you going to expand this to this [Indiscernible]? So we'll take that into mind in terms of the overall clinical proof of concept, payer idea, and the needs that we're seeing. But we had to slow down a little bit and do a lot of work.

And you might have seen, and it's available on our website, a fair bit of the work in terms of different animal models, which are incredibly predictive in epilepsy, on understanding whether or not there was a good scientific rationale on top of the electrophysiology rationale, on top of the molecular rationale to go to this. Then, in the last part, we had to make sure that the FDA was in agreement that we could study in this population. Safety is paramount, making sure that we're actually understanding the populations we're in. So when we checked all those boxes, we're able to initiate the study. I think what is incredible, I would say, is just the level of interest.

If you look into ourselves, if you look into other studies indeed before, if you look into competitive, and I'm going to put that very loosely, there were studies that are going right now, there was no interest in those others. It's pretty obvious by the pace of enrollment that is happening with us and with others out there. And the #1 reason why is that physicians are very confident in the Ada here, just like we are. So it gave us, of course, this extra ability to move things forward. But if I can turn to the business for a second, we are in the business of helping patients.

But at the same time, the only way to continue to help them is to continue to generate proper positive returns to invest in the future. The expansion towards the DEE is like 20-fold what the initial indication for SCN2&8A is, which is incredibly important. But the second part makes not only scientific sense, but it's a tremendous upside in terms of the potential of this drug. Then lastly, I know we keep piling catalysts throughout the year, and you guys might be tired of us having so many readouts.

But we thought it was very important to get that, shortly thereafter, to really, with a fresh, hopefully, approval at that point in time, give the FDA a lot of flexibility to actually look into just the additional data and potentially even qualify for certain accelerated mechanisms that have been available. So all in all, we see this as a tremendous and maybe the key updates today that we're giving in terms of value inflection for investors.

Operator: Our next question or comment comes from the line of Ritu Baral from TD Cowen.

Ritu Baral: A lot of client questions are just around the upcoming power readout and what our expectations should be. Knowing the baseline and knowing the relative baseline of other competitive therapies, how should investors, how should we be looking at placebo-adjusted seizure reduction, the safety profile? And then how might that data then frame the Power2 and 3 studies, given the different doses in those studies and the different dosing paradigms?

Marcio Souza: Great set of questions there, Ritu. So, I think let's start with the baseline, that's what you mentioned. So if you look historically, at least in recent history, baseline for focal seizures in the refractory population, so 1 to 3 ASMs, and you know the drill there on the other criteria, have been hovering around like 9 to 11, 12 countable seizures on the previous 28 days. And I think we're probably a little higher than that, a tiny bit here for POWER1, which was what we're aiming for. We knew these patients were fairly refractory or very confident about the drug.

We also wanted to make sure that once we establish there and have very clear efficacy as we expect, allow us to move incredibly quickly as well towards the ultimate goal of this drug that's being widely available for any patients with focal seizures and in the future, other types of seizures as well. That brings us to the second part of your question, which is the expectations. And I think that it's always dangerous to talk about expectations and setting bars, artificial bars, this late in the game, in terms of like literally like weeks, I would say, before readouts.

But we've been fairly consistent on the expectation here throughout the years is, number one, as the severity increases, I think this is one of the few areas, and we're going to be very excited about science that the new drugs still deliver a lot. We just saw that recently with another program; we expect to see the same, like here, a drug delivered despite being piled up with a lot of other drugs. It is at a higher baseline, so more severity.

And we've historically been giving that adjusted by placebo around 30% or so as quite meaningful because when we talk to physicians, when you look into the active prescription pattern, that seems to be a number that lands incredibly well. And then the last part is safety, as you mentioned. And we're very confident about the safety profile of this drug, both what we're seeing in the blinded, based on POWER1, or also what we are seeing on a blinded basis, POWER2, which was the very last topic you mentioned. So fairly comprehensively, I think we're excited about the upcoming readouts, another card to flip, another program to hopefully accelerate to bring to patients. POWER2 is going really well.

So, as you saw as well in the press release, we reiterated finalizing the study by the end of the year and reading out early next year. So all in all, to think about a potential third or fourth drug or a potential third submission of an NDA or account for this NDA in 12 months is no joke, and we are very, very proud of that.

Ritu Baral: Given that baseline, what about seizure-free, Marcio? Last question, I promise.

Marcio Souza: No, no, like Nick one there. I think, again, we should unblind it. I do feel the #1 thing is really to make sure we have a very solid reduction. But of course, we want to see seizure freedom here as well. It's important. It's something we saw on the RADIANT data, that when you treat patients longer, by week 10, 12, your median seizure gets to 100 percent reduction. So of course, we want to see the more we treat, the longer we treat patients, a very deepening of effect, that's what started seeing. And I'll leave like that, but we're excited with the overall profile.

Operator: Our next question or comment comes from the line of Tiago Fauth from Raymond James.

Tiago Fauth: I had just one quick one on Ulixa. It's also related to the communication plan for the Street on the regulatory interactions still a huge area of focus with investors. So I'm curious what's the level of detail that the Street can expect around mid-cycle review, labeling discussions, CMC inspection scheduling, or anything related to that?

Marcio Souza: Thanks, Tiago. So maybe, again, I'll take another step back here as well. So we are, of course, being communicated by the FDA when the expected mid-cycle meetings are going to happen for both programs, their communication pattern with us, when label negotiation is expected to start and be completed, and the entire cycle. So we have very good visibility from the agency's goals and from the conversations with us in relation to that.

I can tell you that throughout this process, I think a very good shift, I would say, on the FDA is just the ability to really try to keep communicating with the companies throughout the process, and we are seeing that in both programs, which gives us -- I'm going to be cautiously optimistic here about a good level of comfort on how the process is moving on both drugs. Having said that, I think it would not be appropriate for us to give play-by-play. And at the mid-cycle, I think the expectation on our end is that they're going to be like no major concerns, keep reviewing, keep like finalizing, crossing the Ts and dotting the Is.

And if that's the case, I think we should expect very little from ourselves. Of course, if something meaningful happens on those meetings, either on the view of like maybe they want to see something or the opposite. They are moving faster, and maybe they want to accelerate things. I think it would be appropriate for us to have a discussion. But we need to get to that point with both publications to be able to have a discussion. I know you asked Ulixa, but I want to make sure our equally lost child gets some attention here with relutrigine.

Operator: Our next question or comment comes from the line of Francois Briesbo from LifeSci Capital.

François Brisebois: Congrats on the EMBOLD recruitment there. I was just wondering, maybe if you can help us understand, obviously, the patient population size is quite different between IIa and 8A, and then going to broader. But I was just wondering on the broad side, how different are these patients? And my question is geared towards expectations. Is it that the IIa and 8A are so severe that if we look at that data, that kind of sets these artificial bars or whatnot on expectations for the broad DEEs? Or is that a dangerous game based on maybe the heterogeneity of the patients? Just a little more understanding of who you are going after with these broad DEEs?

Marcio Souza: Yes. And thanks. I'll split that question into 2 parts. So, one, it is kind of insane to think this way, but it is the reality of the market. When you go to these patients and to the physicians, and we understand their clinical course and just how the disease is a downward slope, it only gets worse over time for those patients, unfortunately, leading to all sorts of complications and SEP and so on. It is very clear that improvement, any improvement, would be the bar, meaning stat sig is the bar for the ERL study.

Of course, we want to deliver the best possible results for those patients, but I also think we have to be very careful about setting up the bar. And as I said, in relation to the previous study with POWER1 on Ritu's question. So here we are in a situation that is a very large market, but that is nothing. It's the end of the line. If you think about the patients, then over time, we expect to give them a lot. But I think for this study, we need to be happy if we see statistical significance as we expect to and some improvements. Now, to go to the other side of the question, how heterogeneous is this population?

Our recruitment strategy was very clear as to what we want these patients to be diagnosed with. So that's very serious, has to be early, has to have a developmental impact together with seizure onset and a number of countable seizures at baseline. Having said that, we want the most diverse group of patients possible because that's what we're going after. That's what no other drug can do right now. And we accomplished that. By definition, one could argue that IIA and A are harder to treat, but this is more heterogeneous to treat.

So if you can see even half, I would say, what we're seeing on EMBOLD would be just doing -- it's even hard to imagine how big a market that would be. But if we see just stabilization and improvement in these patients, that would be incredibly meaningful. So, on setting it up, what is meant to be a really major opportunity for all of us.

François Brisebois: And maybe if I could sneak in on AAN, obviously, I think the plenary was passed, like about 8,000 people attending. And so can you just talk about your interactions with neurologists and movement disorder specialists, does that trigger any interest for ex U.S.? Can you share what you guys are thinking on the ex-U.S. stage for [indiscernible]

Marcio Souza: Yes. Thanks for reminding us of something that I think we get so excited and so wanting to move forward as always, that sometimes we only stop, slow down, and smell the roses. Yes, being on that plenary at AAN in Chicago a couple of weeks back, and with about 8,000 physicians attending, being the first one to recognize the most important clinical study presented at the meeting. It was very emotional for some of us, for me, certainly.

But the cort the most cort was actually the number of people who came afterwards to us and wanted us to go to their practice with our medical affairs team and present to the entire practice and orordentist start thinking and so on. So it just reinforced now there's a huge interest in ex-U.S. as you can imagine, we believe and to be very clear, this is, first and foremost, a U.S. opportunity right now. We're putting our heads down, and we're executing the U.S. There are multiple implications of current policies in the United States, particularly the pricing policies that I would say don't excite us too much to explore split strategies outside of the U.S.

We wouldn't put at risk the U.S. business. So this is something that someone has to do globally. And of course, we're planning to eventually get there. But we're not really too excited about splitting the geographies with anyone else.

Operator: Our next question or comment comes from the line of Yatin Suneja from Guggenheim.

Yatin Suneja: Congrats. A very nice update. Maybe 2 questions for me. Marcio, you addressed the expectations for POWER1. So the follow-up question I have there is that at least in POWER1, we're going to get data on the 30-milligram QD dose. So could you maybe talk about the potential to capture additional efficacy with the 40-milligram in POWER2? Just love to hear from you, how should we think about the 30 and the 40 if there is any potential there? And then a broader question on the commercial side. I mean, obviously, you are undertaking 2 big launches in the next, let's say, 6 months or so.

So could you talk about the manufacturing, supply chain, all of that stuff, where do you stand there?

Marcio Souza: No, of course, yes, maybe even starting with that. So we imagine when we are planning these launches, we're like, okay, what is likely to happen? And that's how we set our base and how we set the financial expectations, and you see in our forward-looking statements, and overall, you are saying that. And then we go, and we talk to the market, and we start to be maybe a little conservative on some of those. And what if we're wrong on the upper side of that? And then what if we are wrong by several folds on the upper side of that? And that's how we have to plan supply in our view. And that's what we've been doing.

We're glad for Ulixa, for example, to have dual like 2 completely independent drug substance manufacturers. They are being rock and rolled for us to have inventory. We're talking about metric tons of drugs here, of Ulixa, just to give you an idea of scale. This is not like a small scale in general, but a very large scale. And we're also quite happy with the fact that the process is relatively, I'm going to say, in the grand scheme of things, simple, and we've been able to align that with the FDA before the submission. So we're good there. Relutrigine, of course, the scale is smaller for 288, but it's not small for GE.

So we're thinking about that as well, and we're preparing for that for the launch, too. Very different distribution strategies, as you can imagine, a much more full white glove-like one-on-one interactions all the way to the point of use with the relutrigine, and we are building like that. And then on the Ulixa, we want to do a one-to-one as well. But of course, there's a little bit less downstream here. So both the inventory and management of the patient taking the drug have been quite sorted out. If I go back to your POWER1, POWER2 interrelatedness question, 20, 30 milligrams of POWER1, we believe we're going to see very, very strong results there.

But that begs the question: Is there even more to come? So if you look into recent history, very, very recent history, what we're seeing is companies dabbling with the issue of even a little bit more drug, and you trip the wire, and then the drug becomes completely useless from a clinical practice perspective. We saw that in our results a few weeks back, when there are 2 dose and the top dose cannot be used at all by patients despite delivering a little bit more efficacy on paper. But that is not the case here. We know that is not a limitation with Uoraserene.

So when you think about the need of patients and the 3.5 million, not the 30,000 that maybe others are going after, that is the real market we're going after, and it requires understanding the heterogeneity of all those patients. That's why having the ability to deliver meaningful either 20, 30, or 40, you name it, is so important. So as not to create expectations that it could be even better. But of course, by definition, it could be even better there on POWER 2. So we'll get there soon, and we're going to be able to review it. I hope I answered your questions.

Operator: Our next question or comment comes from the line of Kambiz Yazdi from BTIG.

Kambiz Yazdi: Three for me. On Ulixa, with the Essential to Me disease education campaign launched in April, can you give us a sense for the early response from health care providers and how you think this initiative is going to translate into the top of the patient funnel heading into the PDUFA, maybe briefly on relutrigine. I know you touched base on Mario, but how were you able to enroll EMBOLD so rapidly compared to competitors in the DEE space? And lastly, on vormatrigine, you commented a little bit about blinded POWER1, POWER2 safety. How are you handling the investigator's option to reduce the dose of background medication in POWER1 relative to the RADIANT study?

Marcio Souza: Sounds good. I'll try to tackle all of them so I can move on. So Essential to me was something we developed with patients and the way they see themselves. And I think once the reaction from the providers is fantastic. Like, people really love it. They see their patients. It reminds them to act, and so we're very happy with this. It will, and it's already doing a great job on building further our database prelaunch to understand really who would be the first in line here, both on the providers and on the patient. We're going to give more of an update next quarter as well. How did we enroll EMBOLD?

I would say to go back in time, and people would ask, and maybe I'm going to be criticized by the comments, but I'm going to give it a try. We would ask Jordan how it could be Jordan. They would go back to the court, and would train and would understand the shots that worked and the ones that didn't. And it wouldn't take any wins as a win, but as an opportunity for the next win to work. I think we're never going to be as good as Jordan was, but I think we're pretty serious about every single day asking ourselves, how can we do better, because these patients need us.

We're pretty good as well on actually getting sites that have a large number of patients and therefore, have the ability to enroll, and they understand us from the beginning, meaning they understand that our expectation is the highest quality, first and foremost. But also high speeds in terms of you don't sit on queries. We don't sit on the eligibility form. You don't sit on a meeting that's going to happen next week. You need us, we're there immediately. And I think our team is, if I were to say fantastic, they will be fantastic at doing all of this because everyone is here for one single reason is to help these patients. So that's as simple as that.

And I think there was a last question that I actually forgot now.

Kambiz Yazdi: Yes. Just briefly, on vormatrigine, you talked a little bit about blinded POWER1, POWER2 tolerability. How are you handling the investigator option to reduce dose and background in POWER1 relative to what was observed in RADIANT?

Marcio Souza: Yes, absolutely. So what we learned from RADIANT, we've got both pragmatic and programmatic reduction systems in POWER1. One must be very confident in what the investigational drug does to allow for the background to be reduced. Others reduce the investigational drug, as you know, because they don't trust the drug so much, not in our case. So we allow that to happen. I will tell you, it happens partially, which is obviously very important. But I think it was very effective as well. It's the same algorithm for POWER2. I think physicians are very happy with how it's done.

It's very safely done, although very logical, the way it's done, considering the fact that the background, sometimes on a placebo, creates circumstances as well, which is required. So it keeps the blinds, keeps the integrity, but at the same time, manages the study in general. So super happy with that as well.

Operator: Our next question or comment comes from the line of Ami Fadia from Needham & Company.

Unknown Analyst: This is [indiscernible] on for Ami. For focal onset epilepsy, are there any first-to-market dynamics you see if Xenon's product is first to market? Our KOL checks have been overwhelmingly positive for vomacigine, but I just wanted to understand if there are any other factors that may have an impact here? And also, have you had any early discussions with payers on what data you need to generate to support earlier line use?

Marcio Souza: Yes. So I think when you look into the overall market, and we did a lot of work on this, it's very sad in a sense that when you go outside of the very small number of patients that are treated at Level 4 epilepsy centers, and you go to a much larger market outside of that, these patients are failing at very high proportions. They are like switching medications, like they're adding on top of that, and so on. So I said this before, I don't believe that it is a one-winner game here that if we had 10 other drugs for focal seizures, that would be needed. What we have right now is completely inadequate.

Having said that, the biggest complication throughout the years is when you get a drug, and you really can't allow the physician to have the flexibility to tailor for their patients' needs. And I think what we're seeing with vormatrigine is that it gives a lot of flexibility in terms of what can be done, as we just discussed on the previous question, for example, and it's not the case for other potential competitors here. But also pretty confident about our overall pace.

Being a few months behind, and reminding all of you, we were way more than several months behind the other DEE study not that long ago, and now we're reading out soon, and the other study is not even reading out until late next year. So I'm not sure if a few months is really a first-mover advantage. And I don't believe there was ever a mechanistic sodium channel modulator removed from the market, but there certainly was for the other mechanism that you mentioned, and all the safe signals are showing up there as well.

So, I think the physicians we talk to are happy about having more options, but cautious about things that they've seen before not happening too well or working so well for patients on the safety side. So we'll play that. We'll play our press on the market, and I have no doubt we're going to win.

Operator: Our next question or comment comes from the line of Andrew Tsai from Jefferies.

Lin Tsai: Appreciate all the updates. I know we've talked a lot about the EMBOLD study. I did have one small pointed question about it. When you guys shared the IIaA data, 53% placebo-adjusted reduction overall, curious if you saw a consistent seizure reduction in both or each of the 2 DEE subgroups. Maybe that can give investors confidence that you'll see robust and consistent efficacy across the broader DEE subgroup. So, would it be possible to share the seizure reduction in both subgroups? And then for ET, I appreciate all the AAN analyses and so forth.

And maybe based on your ongoing work on a friendlier titration schedule, ultimately, should this be approved, what kind of compliance rate do you expect to see in the real world? How long do you think Ulixa responders could be on the drug for?

Marcio Souza: Thanks, Andrew. Maybe I'll start with ET, and then we can move back to IIA on EOL and in general. So when you ask physicians, and we had a number of advisory boards and this insanely large overall observational study, we asked them how they would manage and what the expectation is. I think the positive surprise for us was just like how comfortable they were in managing what we know to be a tolerability concern that happens on the first few days and first few weeks of this drug.

We're going into this launch fully aware of that being the single most important driver of retention of patients in the long run, and they're incredibly comfortable, and we're actually telling them the things that we thought they could do in terms of like calling these patients and then advising them better, and so on and so forth. So very comfortable with that. Now, how does that translate to overall retention over time and financials? There are 2 approaches here that we can take. One is saying what the things we're thinking about, and that is your classical oral chronic therapy compliance and retention. So starts anywhere from the 60s to 80%. That's just overall numbers out there.

And then what is the minimum to sustain the forecast we put in front of you all to be over $10 billion? That number is way smaller. So I'm not saying the number will be smaller. I'm saying I'm going to have to believe in something to go into a forecast, and we don't need to believe a lot to go to $10 billion plus. And that gives us insane comfort. We also have hundreds, hundreds of patients in the safety database, as you know, that have been on this drug for 6 months, 1 year, 2 years. So that gives us a very good indicator of how persistent all these patients are.

The second question is actually very appropriate to be asked right now, the results on 2A and 8A, despite the fact that the manifestations, the electrophysiology, and the overall clinical manifestation of NaV1.2 deregulations and NaV 1.6 deregulations are very different. The results are quite similar and very good in terms of the overall reduction, developmental gains, and seizure freedom. So it gives us insane comfort that it is so similar across 2A and has all very good points. Thanks for reminding us to make the highlights.

Operator: Our next question or comment comes from the line of David Hoang from Deutsche Bank.

David Hoang: So I just had a couple here. Maybe back to vormatrigine in focal epilepsy across POWER1 and POWER2, I know you're looking at 3 doses, 20, 30, 40 mg. How many of those doses would you like to actually take to market? And what do you think would be the best number for commercial viability? And then in terms of the POWER 3 study, the monotherapy study that you also intend to conduct, could you talk a little bit about how that fits into your broader plans for vormatrigine? And why aren't other sponsors pursuing monotherapy studies like that?

Marcio Souza: Thanks so much for the question, Dave. So 20, 30, 40, when you started S20 for POWER1, and the part is like normally, people start, if you go to the public documents for like other sponsors, for example, everyone is going to be like, " How close to the MESCC50 can I get when you translate that to humans? And I'm going to be pretty close to that because I can go much higher. We can go much higher here. So we're like, where we started the drug is going to be clearly effective. So that's where we started. And where do we end for now, when we believe that's kind of the maximum efficacy?

And I think that's the bull that we are seeing. But a pretty big feedback from the thousands of neurologists that treat this patient is that flexibility is important for them as they're going through different patient types and different comorbid conditions. And so we intend to bring all of those to the market because we believe that gives the highest flexibility to physicians and our largest ability to obtain and keep market share. Now, POWER 3 is a different animal. POWER 3 requires the profile of vormatrigine. So the answer to your question is that others are not doing it because they cannot. Because you need to be able to use this drug as monotherapy.

Now there are steps towards monotherapy. It's not an immediate reduction to monotherapy. It has to be done pretty safely, pretty thoughtfully. But patients fail because they can't be on one mechanism. The only mechanism that can, if tolerated, as we believe here, vormatrigine can truly stop any seizures is by acting on the IS and by modulating these channels. And we're the only ones that do that right now. Everything else is upstream of that mechanism. So that's why the confidence when you have a drug like vormatrigine, as I said in my prepared remarks, this is the most potent and most selective ever developed. So we have this data publicly available for anyone to scrutinize.

So that is the confidence there. What it does is to move from what has been in a little bit of the definition of insanity on how these drugs are developed to get more and more severe patients, smaller pools of patients, and they no longer represent the broader market in those refractory studies. And you're never really addressing the true market, the true unmet needs that are those patients who are struggling to go back to work, struggling to stay driving, struggling to concentrate. A significant number of patients with epilepsy experience disabilities.

They cost themselves, the health care system, and the social security system an insane amount of resources because the drugs they were putting are compounding the issue with the condition. And I think we have an obligation as a company with such a potent, interesting drug to go there and change and revolutionize, as we say, the treatment of epilepsy. That is the long answer to the question.

Operator: Our next question or comment comes from the line of Olson Jay from OpCo.

Jay Olson: Congrats on all the progress. This is Cheng on the line for Jay. Maybe a couple of us. First, on the Ulixa commercialization. Just curious about the feedback from A and the market research you conducted, what do you view as the most important driver of adoption? And then I think at the end, you also presented some data on the cerium channel modulator in pain. So I'm just also curious about your latest thinking around this opportunity and if there's anything we should expect in the near term?

Marcio Souza: Yes, yes, of course. Thanks, Jay. So the most important thing for physicians, when we rank -- and as I mentioned before, and I appreciate you bringing up the question, was very extensive testing and really understanding the details from them. And there are a number of things they really like. They really like the fact that they have never had something targeted for essential tremor. So, having something that the most fundamental mechanism is C-type calcium modulation, and now they have something for that, or soon they're going to have something for that. The second was actually a little bit surprising to all of us.

They absolutely lost the fact that in 2 weeks, for the majority of the patients, you have the ability to have a conversation with the patients and they really have an effect. They just don't have that right now in a sustainable manner. They like the fact that we tested the durability of the effect in Study 2. And I would say all those things together, and there are many others, really are going to be key drivers of adoption. And as I mentioned on one of the previous calls about like inventory and building, if anything, they're giving us indications they're going to prescribe to more patients than we originally thought they would.

And then the second part of your question about our pain program. Well, I think we've been, as you can imagine, we're a CNS company. We need to look into areas of science that make sense for us based on our technology, on the one hand. On the other hand, we do have a fair bit of things that are moving forward as we discussed today, and many more catalysts to come. So we've been taking a measured approach in terms of exploring a number of other areas in science where our molecules and our platforms can play a significant role. And at AAN, we did present some of the work we've been doing in pain.

And you will hear more from us in the future about how we are advancing quite significantly in that regard as well.

Operator: Our next question or comment comes from the line of Douglas Tsao from H.C. Wainwright.

Douglas Tsao: Marcio, just starting with EMBOLD, I'm just curious, congrats on completion of enrollment. Obviously, demand was very strong. I'm just curious if you have insight into the subsets of patients that you received? And were there any particular ones where you saw very strong demand to reflect sort of the magnitude of unmet need, because obviously, for so many of these, there's no approved therapy, and physicians are just basically trying to figure out as they go along, using sort of off-label ASMs.

Marcio Souza: Yes. Doug, I'm going to be honest, when we went to the sites, and we talked to physicians who presented the protocol. Maybe what I haven't said in the call so far is that we disappointed a lot of physicians by telling them, no, no, no, you've got to stop. You can't enroll more patients in this study. We really got there pretty fast, and it seems like we have a deep understanding of this, exactly what you just said. There are so many patients out there that there is very little or nothing they can do, even patients who have other drugs technically approved, but they have failed already, or they try to have a suboptimal response.

So it is very broad. Both the phenotype and genotype of patients we got here. And it is within what we expected. And unfortunately, maybe this is a coup in apology, we couldn't get all the patients that wanted to be on this study. But I think our promise is if the drug works, we're going to get this drug to them in the near future. So really, really happy with everything and all the dynamics here.

Douglas Tsao: And if I can, on a follow-up in terms of vormatrigine. With POWER1, I'm just curious, do you have any insight in terms of the discontinuation rate so far? Because obviously, I think in RADIANT, there were some discontinuations, but we certainly heard from clinicians that they had patients who maybe dropped out, who they would have provided some additional counseling, just given the robustness ultimately of the drug, they would maybe encourage them to stay in. Additionally, given the fact that you titrate up in POWER1, if we're seeing any evidence that is having an effect?

Marcio Souza: Yes, absolutely. So we're pretty happy with how we got reduced, I would say, the overall discontinuation here in terms of the historical with the program. I think some of the points you mentioned, people get more experience with the studies, and so on, they get more comfortable managing. So I'll say I think we're very comfortable with that. I think we're very comfortable with the new benchmark as well, when you consider that drugs people are excited about have like 22% to 25% discontinuation with a further 25% dose reduction on the top dose. That's definitely not what we are seeing. So we think we are very, very competitive here, considering recent competitive events.

Operator: Our next question or comment comes from the line of Danielle Brill from Truist Securities.

Unknown Analyst: Tyler here for Danielle. My question is regarding the total addressable market in essential tremor. So up to 7 million patients have essential tremor, but you recently said that there are approximately 1 million actively seeking treatment. So what's this gap between the predicted prevalent population and those seeking treatment? And with that, is education still needed in the field for more accurate diagnosis? And do higher volume academic centers typically have a more accurate diagnosis?

Marcio Souza: Yes. So there's about like 2 million to 2.5 million patients right now, either who are being treated and seeing a physician at this moment or just done it and are sitting on the sidelines. So when you go from 7 to, let's say, 2 to 3, it is a drop that is not unheard of. I'll say there are many, many reasons here. It is not a misdiagnosed problem, and I want to clarify that.

This is mostly something they know and they're either not speaking publicly or disclosing or discussing because they know there's a stigma, there's effect I think we just saw this week, Senator Collins speaking about her diagnose of essential tremor in the sense of people attacking that she might not be fit, which obviously is absurd, because this is a progressive disease only of movement, for example, but people are afraid of talking about things like that. It is a disease that, for the most part, runs in the family. So people are aware. It is a combination of 2 factors. One is the progress. It's how quickly and how far in the disease patients are.

We call that the level of feasibility, and that's what gives us about $3 million. And the other is society, sometimes not being too ready for someone to raise their hand and say they have a condition. I think the last one is one where you have 2 or 3 family members, and a physician tells the first one, " There's nothing I can do right now because there are no good alternatives available. You did engage the other family members with ulixacalamide coming to the market; hopefully, soon those dynamics will change. So we bring this to the forefront.

One of the reasons why our campaign is called Essential to Me because it's really what is essential for the patients' death. That's what we want to awaken to that.

Operator: Our next question or comment comes from the line of Brian Skorney from Baird.

Brian Skorney: You alluded to the opportunity to develop Ulixa and the oral T-type calcium channel antagonist in indications beyond ET. Obviously, you're pretty full with NDA reviews and running another few pivotal studies. So maybe it's a little bit in the background. But just wondering if you had any updated thoughts on the exploration of other indications where Ulixa could have an impact? And if there's any time frame you can provide, where we might hear an update on that.

Marcio Souza: Yes. Brian, we selected 2 other indications we're going to be going through. We're just going through the last, I would say, checking everything here, taking the time, and making sure that we can discuss a little bit more publicly. We're discussing the format of that as well, whether it's an R&D Day or if it's a series of calls and experts with us. So sight just for a bit, and you're going to be able to talk about that. We are very excited, both scientifically, on the patient side, and market potential for either of those indications.

Operator: That's all the time we have for Q&A at this time. I would like to turn the conference back over to Mr. Marcio De'Souza for any closing remarks.

Marcio Souza: So thank you very much, everyone. I'm sorry for the questions we couldn't take on today's call. I think we're running a little bit ahead here. An incredibly exciting way to start the year. As you think back over the last 12 months, so much happened in really moving the needle for so many patients. Yet, another study they're finalizing, making sure that we flip the card, make sure that if there is a benefit, we're going to get that as quickly as possible. This year, with EMBRAVE Part A being positive, EMBRAVE 3 recruiting really well, EMBOLD coming up, POWER1 coming up, POWER2 coming up, new indications, as Brian just asked. So we're full steam ahead.

The focus is very clear, is to deliver as much value for everyone, including our shareholders. And we promise you we'll have our heads down on the execution here and get everything done. Thanks for the interest, and we're going to be talking to you soon.

Operator: Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.

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