Praxis Precision Medicines, Inc.

Speaking about the NDA review, the FDA completed its mid-cycle communications with us and are very pleased with the progress and discussions with the agency. In that meeting, the agency identified no efficacy-related significant issues and stated that it does not plan to request an advisory committee meeting. I would characterize the discussion as expected and very forward-looking. On the commercial build itself, leadership is in place and all core capabilities are where we expect it to be at this stage. We will be ready ahead of PDUFA to launch ulexacultamide for ETC patients. We're set up for a very successful launch and continue to think many years in the future as we intend to continue to serve patients with ETC and other neurological conditions. As part of that, You should expect updates from us in the near future about life cycle opportunities for T-type calcium channel inhibitors. One of those steps is the collaboration we just announced with Reimagine, which would extend the reach of Alexa further. Their work is about expanding the value for patients and practices way beyond the initial launch year. Turning to relitrogene. SCN2A and SCN8A are among the most severe epilepsies we know of. Fissure onset in infancy, profound developmental delays, and no approved treatment. The addressable population is roughly 10,000 patients in the United States. As we disclosed last quarter, we submitted additional sensitivity analysis of existing clinical data, and the SCA deemed that submission a major amendment. and the review period was extended with a new PDUFA target now off December 27th this year. In the mid-cycle meeting for relutrigine, very similarly to Ulexacalpamide, as I just discussed, the agents also confirmed they do not intend to hold an advisory committee meeting. If approved, relutrigine would be the first therapy for SEM2A and 8AD and would be eligible for a pediatric review voucher. Just like for ULIXA, launch preparation here is further along than the calendar might suggest. Commercial and medical teams are fully hired, the supply chain is established, and you have to build a comprehensive patient support program, all pointing to a very structured and successful launch. The broader opportunity keeps getting clearer. Enrollment in Emeralds, our study in broad DEs, exceeded its target, with approximately 200 patients enrolled spanning more than 50 distinct genetically defined etiologies, amongst many others not genetically defined. There is a trial population that did not exist as a cohort even five years ago. Assuming the study will be positive and the initial review for relutrigine in 2A and 8A, also positive, Emerald would serve as the base for supplemental NDA approval in 2027. It's also worth mentioning a quick regular update that spans both programs. During the quarter, the FDA conducted a bimon inspection of Praxis as a sponsor for both ulexacalcmide and relutrigine applications. The scope was very comprehensive. including corporate and clinical operations, safety, reporting, data integrity, statistical analysis, and the interim analysis for both programs amongst other areas of the BiOMO program. We're incredibly pleased that the inspections concluded without any findings and therefore no Form 483 was issued. Considering how complex both programs are with multiple studies and the first-in-its-kind decentralized study for IT, as well as the interim analysis, we're extremely pleased with the outcome of the inspections. One note on how it communicates from now on. Given the stage of discussions on both applications, we do not intend to provide further regulatory updates until the expected action date. I would ask you to read our silence between now and January as discipline rather than a signal of any kind. Let me turn to vermatrogen. In June, we reported top line results from Power One in a highly refractory focal onset seizure population. As you know, the study did not meet its primary endpoints of reduction in monthly focal seizures frequency from baseline to week 12. It did meet a key secondary endpoint with a significantly greater proportion of patients on vermatrogen achieving at least 50% reduction in seizure frequency. That result tells you something specific, and you have spent the last several weeks making sure we took the right lessons from it rather than the comfortable one. The responder findings say the drug is doing something real in a population where very little works. The primary endpoint myths say our dose and a few elements of our design were not matched to the question we're asking. Those are design problems and therefore fixable. We're finalizing the plans to amend and revamp both Power 2 and Power 3, informed directly by what Power 1 taught us about the dose and entry criteria, and we intend to have both studies up and running by the fourth quarter of this year. We will further describe the amendments and impact on the design once they are final in the very near future. Switching gears to Alzheimer's. In June, the FDA granted us BTD designation for Alzheimer's for seizures associated with SCN2A-DE caused by gain-of-function variant based on the results of the EMBRAVE Part A study. That's our third breakthrough designation since July last year. Three designations across three different assets on two different platforms. It's basically unheard of for a company like Praxis. We're taking advantage of the access to the FTA that the designation give us and discussing a comprehensive plan with the agents in the near future. Parallel to that, Embrave 3 continues to enroll well with top-line results expected next year. We're incredibly pleased with all the progress made in all fronts this quarter, and we look forward for a successful rest of the year. Let me now turn the call to our CFO, Tim Kelly. Tim?

Thank you, Marcio, and good morning, everybody. Thank you for joining today's call where you've heard about the good updates that we have going on. I'll provide a quick summary of our second quarter financials. In Q2, our operating expenses were $96.9 million, with $69.4 million of that for R&D and the remaining $27.5 million for G&A, which compares to $76 million in operating expenses for the Q2 period in 2025. During the second quarter, Praxis spent $78 million in operating cash, compared to $55 million in the second quarter of 2025. with the increase reflecting greater spend in both R&D and G&A. We expect G&A will pick up more in the second half of this year to support our planned upcoming launches. This will be driven by adding two teams of commercial field-facing headcount, rolling out disease state awareness campaigns, building sufficient inventory, and ensuring solid business systems and infrastructure. We ended the second quarter with $1.4 billion in cash, cash equivalents, and marketable securities, compared to $926 million as of December 31st, 2025. And we maintain that this is adequate to support our runway into 2028. With that, I will hand the call back over to Marcio.

Thank you, Tim. Really appreciate the updates. Now I'm going to move into Q&A.

Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your phone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please limit one question per analyst and hop back into the queue for further questions. Please stand by while we compile the Q&A roster. Our first question comes from Yasmine Rahimi from Piper Sandler. Your line is open.

Good morning, team. Congrats to an incredible update that I think was very, very timely and important to us, especially as some bears have been creating some noise around, you know, APCOM. So thank you for letting us know that you had a successful mid-cycle review along with inspection. Given now that that is behind us, maybe help us understand sort of with the sales team that is being hired for Ligurigine. What is the phenotype of the sales force that you have in place? What is the size of it? And how do you see the cadence of hiring for Olexacultamide? So, Tim, that was really helpful. But if you could dig a little bit deeper around some of the matrix and if you also envision sort of patients have been warehoused as we're getting very close to launch early next year. Appreciate your color and congrats again.

Thanks, Yaza. Absolutely share the sentiment that you just expressed there, right? Like incredibly complex programs, as we discussed on the remarks. To actually check all the boxes, collaboration with the FDA has been exceptional. The real questions we got throughout have really been, I would say, very straightforward and really very similar to what had been discussed before publicly. So we checked that box quite nicely as well. And of course, the cherry on top, it's always good to get the FDA in the house, checking everything, making sure that they agree. We always knew we were doing everything correctly, but that they agree with our assessments that from data integrity, documentation, communications, procedures, safety of subjects, in these studies, everything was checked there. So we turn a page to talk about what we really like talking about, that the millions and millions of Americans that are not served currently in the United States, we've been very diligent hiring a world-class sales, marketing, market access, medical, of course, Tim at Braxis, and I can say this is probably an opportunity of a lifetime if you are in one of those positions to launch these drugs to transform patients' lives. But I'll hand over to Megan to discuss a little bit the phenotype and what we are seeing and the stage we are.

Thanks, Marcio. So, yeah, as Marcio was sharing, right, not unexpectedly, these are hot launches upcoming. They each represent the first targeted therapies Indications with huge unmet needs. So it's allowed us from a hiring perspective to be very selective and we're incredibly pleased with the caliber of the talent. So certainly from the phenotype, individuals with multiple launch experience, the rare neuro space, the hunters that are going to go out there and really do a phenomenal job for us. And in the case of Lutrogene, now we've got the team hired and trained so we have the next few months to really be are active in doing the account profiling, which will set us up quite well from a launch readiness perspective. And then the Ulexa Field Forest buildout is well underway and also on track for where we'll be from a launch perspective.

Thanks, Megan. Thanks, Cialis, for the question.

Thank you. Our next question comes from Ritu Baral of TD Cowan. Your line is open.

Good morning, guys. Thanks for taking the question. Marcio, I wanted to dig down into your comment about the mid-cycle, the ULICSA mid-cycle review meeting, if you'll let me. You mentioned the word forward-looking. I guess first, could you comment on if there were any surprises during the meeting, any new topics that were unexpected? and two, I guess, how do you define what you're calling forward-looking? Have you been able to discuss what we spoke of previously, which is the potential inclusion of alternate titration regimens to improve the ULIXA experience? And if I could ask a quick follow-up to that last point, the ULIXA experience, what aspects of commercial launch prep are you preparing to optimize that commercial experience to optimize compliance? Thanks.

Yeah, absolutely. And I appreciate the vagueness of what forward-looking might be there. So I'll take that one. But it was not meant to be vague. It was really meant to be when you look into forward-looking here in the context of this application, right? So we are late stage now approval, labeling, promotion, like making sure these patients have access. I think that that's what I meant by that in the conversation. I would say, Richard, the conversation itself in the room, it's a rare type of feeling when you are in a discussion with the FDA, at least in my view, where you actually feel very peaceful. and that's the way I would describe how I felt on that discussion where they know for a fact that there will be incredibly transparent collaborations, be incredibly high and really all the elements that are necessary to make a decision have been on the table. So on your sub-question about surprise, I would say not really. Maybe my surprise on the meeting is just How much of the discussion turns into proper use, I'm going to call, of the drug. And by proper use is when you discuss labeling and things like that normally later in the process, all you're really trying to do is proper use, right? So when you are actually marching towards proper use in conversations like this, I consider exceptionally positive the discussion, the level of, collaboration and integration and the understanding of the application, the depth and the breadth of the discussion, the number of people in the meeting, the presence of leadership and the support from leadership. All of that, what I meant is it is an application that matters for them as much as it matters for us. And it was good to see that overall. The topic of titration did come up to your point as completely expected, right, as something we proposed. to have. And once again, I was positively surprised by how much further along our alignment is in that regard. While I cannot and should not predict what's going to end up staying on the label, I can tell you right now unequivocally that there is a very good understanding that when patients start to lexical optimize, They will sometimes, in about 30% of the case, have some tolerability issues that does not transfer to safety issues. But if they stay on that, that goes away. And they have this quite phenomenal, in my view, efficacy that is just not there for any other compounds. And any reasonable person, and I think that's incredibly reasonable, and certainly we believe we are, will look into that as an opportunity to maximize the suffering on this incredibly difficult indication by figuring out a way for patients to get there. And I think we're really, really close to figuring that out. How this translates to commercial, and I'm going to hand back to Megan on this as well, you can imagine that 70% of the patients on 7 million or even 2 or 3 million at launch anyone who would say plenty for our very, but we want every patient to have the best possible experience and you want to make sure every patient stay on drug if they desire to and if their physicians believe they should. So maybe Megan can talk a little bit about what we are doing there.

Sure, thanks Marcio. So maybe just to recap again, the focus out of the gates for the launch will absolutely be on ensuring the high quality first experience so that we build the physician confidence and ensure that we have that durable patient persistence. I think in the context from the provider's perspective and as we've been doing advisory boards and also engaging with the physicians, I think it starts with them setting up that first conversation with clear expectations. And as they see the Ulexa calcimide data, the ability to tell a patient there's going to be a rapid onset of effect with a meaningful change and that there might be some tolerability issues, which as we hear from the neurologists, they're very comfortable with managing the patients through that. In terms of some patient programs and services that we're building, Tim mentioned in his remarks, we're well underway in establishing the infrastructure we need to support this. We're basically building a hub of the future. which is fully integrated from the front end to receive the prescription all the way pulling through the channel to ensure that we have line of sight to where we are with fulfilling that first RX. But then also having certain programs and services on the SP, the pharmacy side with our integrated network to ensure that we're able to deliver the support to the patient to get them started Thank you. Thank you.

Our next question comes from Francois Brisebois from LifeSci Capital. Your line is open.

All right, thanks for the question. So just on relutrigine, I was just wondering, I think you mentioned that there's about 50 separate genetic etiologies involved here. Would you say that the study population is relatively enhanced for indications which either have a history of sensitivity to sodium channel blockers or not?

Yeah, thanks, Frank, for that. Hand over to Steve to discuss a little bit.

Yes, I mean, you know, looking at the size of the trial, that spread of etiology is precisely what you would think to get when you look at the distribution of prevalence in that group of patients. And the precise mix of people that we fully anticipate would be pharmacosensitive to a sodium channel mechanism is represented in that cohort.

Okay, great. And then you mentioned it all. Can you comment on the powering of Emerald here? I think based on the study number, is there like a placebo kind of level or a median percent change that you're looking for, for Statsig?

Yeah, but with the caveat, right, that two like multi, both genetically diverse, you know, genetically diverse studies have not been run So far, but there are many that we can borrow from. And when you go through that analysis, I think what we know is like there are kind of three levels here. So the first, when you look into the overall response and let's define whatever, 50%, that benchmark is very clear. It's like very small for placebo. Of course, these patients are so severe. I'll give you a number. The median baseline Countable seizures in emeralds is over 50 for 28 days. So imagine that kind of burden and just how little it is, the possibility that these patients are going to naturally regress. The second is, as we move upwards the ladder, like 75% response, 90% response, those numbers become very, very ridiculously small for placebo. So as we are looking into the distribution, It was very simple, I would say, to model from a power perspective. And I would say very straightforward, the expectations, as you can imagine, as you heard from me, before you hear from Steve now, we're very pleased not only with the a priori powering, but quite importantly, the a posteriori mix of patients that are pharmacosensitive to the mechanism. So stay tuned. Soon to come up the results, but I think we should be as bullish as we are on what we're going to see on the other ends.

Great. Thank you very much.

Thank you.

You bet.

Our next question comes from Kevin String of Goldman & Sachs. Your line is open.

Good morning. I wanted to ask on... For Matrigine, you alluded to the design being more important versus the drug itself. Do you mind walking us through sort of some of the specific learnings from Power One on dose redesign that gave you confidence to restart the program? Thanks.

Yeah, absolutely. So we're going to reserve it, and I hope you don't see this as hedging because it's not. Since we're going to be discussing this a little bit more in the future. But a couple of things that we as we look into like in a very detailed and at the same time keeping ourselves from seeing things that are not there for really disciplined approach to what we're going to do next, right? Looking about the value right now, at least external value for the company, one could argue for theft of the value is on the Alexa and religion. So, of course, there's a huge potential for upside and huge residual value for vermatrogen, but we really want to measure that. That's one of the reasons why we're not focused today, call on varmints. Dose clearly played a role. Duration added dose clearly played a role. We sometimes say dose, it looks like it was only the 20 or the 30, but actually six weeks and six weeks play a role and I would say a pretty significant role on that. I think a few other things that you're going to be hearing further including like the number of failures that was extremely high to prior medications that could be tightened up and a few things here and there. But every single parameter, maybe that's the method I'm going to leave you with, that we're looking into are very easy to adjust and to fix. And then once we do, without overstretching, without drinking the Kool-Aid, without like seeing things that are not supposed to be seen there, the effects on the other side for Power 2 and of course eventually Power 3 are X or higher than what I would expect for this drug on those populations. Great way to look into this. We're finalizing a few things internally and with our key advisors. You're going to see an update, a fulsome update about that in the near future and we're starting out this study.

Thank you. Our next question comes from Tiago Foth of Raymond James. Your line is open.

Great. Thanks for taking the question. Just on Emerald, right? You know, for Dravet, conventional sodium channel blockers are counterindicated. Sometimes they can make seizures worse, yet you had really strong preclinical data in Dravet models, right? So what does that example tell you about the mechanism relative to conventional sodium channel blockers, and what does that imply about the potential to work across other DEEs? We've been getting a lot of questions on the enrichment criteria that you have on seizure burden being enough to offset some of the unknowns or risks from non-ion channel DEs that can be in the mix of Emerald. So how should we think about that overall?

Yeah, absolutely. I'll start with and then hand over to Steve here, Tiago. The first is, I find it a little ironic, I'm going to say, to be the classical me in calls like this. Then no one asked about how many serotonergic mutations are when this is being discussed, the serotonergic one, but it's very easy to say sodium channels for us. So maybe one must revisit their own understanding of neurobiology. But having said that, I'll hand over to the person who really knows neurobiology here. That's not me, that's Steve.

Thanks, Marcio. I think when you look at the role of sodium channels in determining The behavior of neurons normally and in epilepsy, clearly they are the gatekeepers of excitability in a neuron. And because of that role, if the sodium channels themselves are altered in their behavior as a result of mutations as we saw in the EMBOLD study, they are a clear target. But beyond that, they are also the most downstream element in the etiology of other disorders that result in DEEs, whether it's other genetic mutations or acquired conditions. Because of that very unique role, they are also targets where a lot of the physiology converges. So we got a lot of confidence that it doesn't really matter what the etiology is. Even in the cases of loss of function, and there's always a lot of chatter about that, clearly, even though we've lost sodium channel function as the primary mutation, We still have excitability issues. And the way to control excitability is through modulation of sodium channels. When these loss of function mutations occur, that can result in the upregulation of other elements in the neuron. So we're confident of that. Our preclinical data shows that. And this is all because sodium channels are concentrated in a very specific part of the neuron where the axon emerges called the axon initial segment. It's a pretty much crystalline structure of sodium channels and other elements. And that is the little part of the neuron that decides, from my experience from everything that's upstream, what am I going to do? How am I going to respond to that input? And we know that that program is modulated a lot by sodium channel modulation. And one other thing I want to say about sodium channels is the manner in which the sodium channel modulator interacts with the actual sodium channels themselves is very important. And we know, we've talked about this a lot, that the mechanism of action and the profile of relutrigine distinguishes itself from any other agent in the market now. And that was the initial therapeutic hypothesis we started with relutrigine, and we are following that through the trials right now.

Yeah, honestly, very helpful. Appreciate it.

Thank you. Our next question comes from Douglas Zou of HC Wainwright. Your line is open.

Hi, good morning. Thanks for taking the questions and congrats on the progress. I guess, Marcio, I just want to maybe start with Formatrogene for a minute because it was interesting that you sort of are going to be restarting both Power 2 as well as Power 3. I'm just curious, do you think that those two studies would be enough to support a potential filing, just given the fact that they are going to be very different Thank you.

No, thanks, Don. Yeah, we do. That's maybe the short answer to that. There are steps between now and then to have conversations with the agency and to discuss exactly which label potentially that would result. But the bottom line is both from a historical perspective and most importantly from a policy perspective, as it forms up right now, and even considering like the progressive nature of the division that all epilepsy falls within right now as just restructured a couple weeks ago, I think we feel incredibly bullish about it, but should be seen.

Okay, and if I can ask a follow-up in terms of the richer gene. I'm just curious because obviously that program, in particular with Emerald, is enrolling and there's obviously the Beficazorin program ongoing as well. And I'm just curious if you have heard any feedback in terms from clinicians, if there's any kind of What types of patients are referring to each particular study? Is there any kind of subconscious enrichment ongoing in terms of picking a study in which they think a patient might be best to respond to? just given the different MOAs of the drugs. Thank you.

I get it. And I would say we always have to take with a grain of salt anecdotal conversations we have with one or two physicians here and there. But it is not unexpected, right, that you would say, oh, no, like let's say we will start with serotonergic here. There are drugs approved. There are a lot of stuff that's being done on that space. Hand-to-hand combat with multiple drugs for Dravet and LGS. Yeah, if we're going to try another drug, let's try on the ones that are there. I would humbly say that, yeah, that's maybe okay for trial execution. It's a terrible strategy once you get to the markets, but I'll leave it there. I think likewise for us, the The Emerald White, as we said, like about 200 patients finished randomization like a while back. And it is kind of obvious by what Steve just mentioned that when you look into the final mix, that either by chance or not, that this seems to be some of the most potentially active on this mechanism historically. So whether or not there was a conscious or unconscious, kind of segmentation when there were sites that were enrolled in both studies. It happens naturally. You fast forward a few years from now, both mechanisms work, right? I think we know that. And on a market with like anywhere between two and 400,000 patients, the discussion is bringing on 10 other mechanisms, right? Like this is a number one, should be a dream for anyone on this space. It's an ability to help in are incredibly sick kids and young adults to control seizures. And any one of us that thinks that one mechanism is going to do this should be institutionalized. So I think it is more than reasonable to expect that multiple mechanisms are going to be not... I keep going back to the same thematic. You heard me saying this a thousand times. I'm going to do a thousand and one. The zero-sum game idea, NG is an epilepsy. is purely serving to people who don't want patients to get drugs. It has nothing to do with either drug developments or market potential. So if anything else I'm going to say, I'm going to be cheering every day for Lumevac to be incredibly successful, just like we're going to be, so we all can help patients with these conditions.

Okay, great. Thank you so much, Marcio.

Our next question comes from Andrew Tsai of Jefferies. Your line is open.

Hey, team. Good morning. Thanks for all the great set of updates. Back to essential tremor, there really, to me at least, seems to be a chance maybe ET could be approved earlier than expected, especially if this mid-cycle review is done, inspections are done. Is it the right thinking that you will be entering final labeling discussions soon, or if not, Can you just remind us what the key steps generally are from here? And then how prepared would you guys be to launch in Q4 if there was an early approval? Thank you. I appreciate you might not be able to share too much, but that's just what I'd ask. Thank you.

I appreciate it. So the next four more steps here are the quick late cycle discussion. I'll tell you that's in the books. Label negotiations, that's in the books. So the reason why we mentioned in my prepared remarks is that we're not going to be giving updates because you can imagine that this discussion as we move forward is very dynamic, right? So there's a lot of back and forth. There's a lot of really cool discussions there. We set the goal to be ready for launch way ahead of the Dufa for multiple reasons. One, it's the right thing to do. Two, thanks to a lot of you listening to this call, we have the capital to do it. Three, I would challenge absolutely everyone in this culture to name one market with millions of Americans that don't have a treatment right now that are getting every single day requests from physicians and patients to when is this drug going to be available. So it's just a responsible thing to do. So we'll be ready. We are basically ready. And we're going to continue to be ready to maximize in the case of the great fortune that the Asians finished the review earlier, and we are blessed with that approval earlier than the PDUFM.

Thank you. Fingers crossed. Thank you.

Exactly. Thank you. Told us all.

Our next question comes from Yatin Suneja of Guggenheim. Your line is now open.

Hey, guys. Thank you for taking my questions. And again, you know, excellent updates today. So just staying with the essential tremor, could you maybe talk a little bit about the PAIR work you have done?

Marcio, in the past, I've talked about pricing, love to get the feedback that you are hearing from the PAIR perspective.

And in terms of the step at it, how should we think about it? I mean, most people are on genetic stuff, so there should not be much. Love to sort of understand all of those dynamics. And in terms of the commercial build out, could you maybe outline for us when is that Thank you so much.

Yeah, absolutely. So from a payer perspective, very, very active. So we did a lot of pre-work to shape our general understanding. Of course, that is a lot of analytical work that can be done. We've done that benchmarking work. and we moved on the last several weeks to a different phase, right, where both proactively we want to talk to some of those plant administrators, but I would say the latest wave is that they want to talk to us. And I would say there was a lot of those interactions. I would even argue I was positively surprised with one, their understanding, that absolutely there's a need here and that they're not going to put a lot of stuff, not a lot of blocks out in the way. The second is just like they want to be right at day one, just like we want to be right at day one. So that's good news. Our planning assumptions includes step edits through Propanolol. Not at all, by the way, what we're hearing across the board is going to happen. It's just a prudent thing to do. look into this. Now, we know we did extensive work here from a medical perspective and claims and so on that a lot of these patients, they're just supracardiac or something else that it prevents them from ever going into a beta blocker. So about half of the market cannot magically take propranolol. One can call that low-hanging fruit. but I guess you call a million patients low-hanging fruits a little bit oxymoronic, so I'm not going to do that. So that is a very clear part of the market. I think the other parts, they just have exposed to that. I'll remind everyone on the stratified, predefined use of propranolol on the Essential 3 study showing that on top of propranolol, Ulexacalpamide is incredibly All right. And so that is really no restrictions here one way or another. And welcome. Do we believe that in the long run that's going to be needed to stay involved? No. But that's a belief. We welcome all the patients that they want here. And physicians are incredibly excited about hearing that, which is normally what payers actually want to hear. So a lot of work is being done on the payer space. I know you asked about pricing. I think the more we talk to payers, the more we realize that our initial pricing assumptions are very well, I would say, grounded. We talked about a little bit over maybe $50,000 to $100,000 per year. There was a lot, as you know, from clients of yours and from people without you, a little bit of pushback, and you actually go that high. I think right now, while we're not going to disclose the price specifically, I think we're actually very confident that that's the right range to operate in general.

Thank you for your question. Our next question comes from Kambiz Yazi of U.S. Bancorp BTIG. Your line is open.

Thank you for the question. How are you thinking about the genus efficacy in emerald relative to what was observed and involved?

From a biological level, how should we think about performance in broader DEs compared to the SCN2A and NAA population? Thank you.

Yeah. So, thanks, Kambit. Good to hear from you. I would start with the what is necessary. and then what is possible. And I think those are two completely different things here, right? I mentioned earlier in the call on the background seizure burden for these patients, right? Like it is absolutely insane. I cannot even imagine as a parent to have to deal with something like that. These patients tried and these parents tried everything they could possibly imagine on those. Logically, no matter what one wants to believe, reducing consistently a part of those seizures and therefore statistical significance when you think about a study, that should be a bar, right? So the bar here is significance on the study. But of course, who wants to go above much, much higher than the bar, right? So bar for success, no doubts whatsoever. Physicians, patients are saying, Help me control a little bit better. Let me give a little bit more hours without like being on top of the skids, nonstop, afraid of complications with that, you name it. And that would be a big win. Biologically though, by what Steven just discussed, there are reasons to believe that it could be similar, if not better, than what you're seeing on in both. I think it's hard to imagine, right, being better than both. But we need to stay true to the science and to what we are seeing so far. We're going to discuss a lot more about this in the near future as well. But again, going to have to stay true to what is possible. Not necessary, but we'll love nothing more than help these patients to an extreme. Thank you so much. You bet.

Our next question comes from Jay Olson of Oppenheimer. Your line is now open.

Oh hey, congrats on all the progress and thanks for taking our questions. We have another relutrigine question and just wanted to follow up on something that you've commented on in the past, Marcio, that you've seen in the pooled mask data from Emerald that you've observed dynamics that are profoundly different from what a meta-analysis of historic DEE placebo groups could accommodate. Can you talk about the most important factor behind this observation and how would you compare the information in proportion of patients with a 50% reduction versus 75% reduction versus 100% freedom from seizures?

Thank you very much. I think that's all those parameters you mentioned, right? This continuous of response, 50%, 70%, 75%, 90%, 95%, whatever you want, 100% are incredibly important. And we've been tracking and we've been, I would say, quite pleased about the entire distribution. Maybe one point here that we haven't discussed as much It is quite interesting as well to see what happens when they transition to the open label. And studies have been going on for a bit and we rose relatively fast. So there is a very large proportion of patients that have multiple months now in the open label. So when you put all of that together, the initial response of the double blinds, the information we're able to get from the open label, I would say they depart A lot from what historical expectations would be. And hey, who here hasn't been burned by blinded data, right, from the first rock? So I'm not saying this is like completely proof of any possibilities of not being a misread, but it is just very hard to believe that we would read this incorrectly considering how severe this disease is and how high the seizure burden is. Very happy across the boards, but we're going to stay vigilant until the end of this study.

Super helpful. Thank you.

You bet.

Our next question comes from Ami Fadia of Needham and Company.

Hi, good afternoon. Thank you for taking my question and congrats on all the positive updates this morning. I had one question on Alexa and one follow up on Emerald. As you think about the update of Alexa, can you talk about the mix of patients that you expect across maybe the commercial Medicare, Medicaid setting and where do you see the initial patients coming from? Is it sort of older patients that have been sort of, you know, suffering with ETE for a very long time? Or do you also expect younger patients to start to take Alyssa, you know, earlier in the launch? And then with regards to the EMRL study, across the 50 etiologies that you talked about, from a mechanistic perspective, is there a reason to believe that the Response rates would be similar, or could it be varied across, you know, across the different etiologies? Thank you.

Yeah, no, absolutely. I mean, the, so for, this launch is going to likely have like several states. If you look into the, I believe we've been quite responsible defining the addressable population at time of launch around 2 million patients in that is mostly, I'll say three quarters or so of those patients would be the Medicare, Medicare Advantage, like arguably slightly older patients there. Maybe the phenomena that we are seeing more and more is the family members, right? And the interests of those patients. And so I would say for the phase two, very likely we're gonna see is like a migration continue to increase these patients on the 65 plus. There's also a lot of the 40s to 65 patients there. Of course, there's a different Bayer mix, there's a different dynamic on those patients. Maybe the part we don't talk as much about, we kept this number static, but it's not stasis. The population demographics in the United States, and globally, but particularly in the United States, is shifting quite a lot. And when you look into the prevalence of essential tremor in the overall population, it's a little bit about 2, 2.5%. When you get to 60s, that is about 2.5 times the overall prevalence. And then about every 10 years after that, it doubles. So we haven't discussed, but we're going to hear discussing a lot more, is actually the completely organic growth of these markets that is about double digits. And we just don't have drug launch on multi-million patient markets growing organically as a market, double digits are moving forward. So that changed a little bit, the mix. I know you had an Emerald question there as well. Oh, the efficacy across the etiologists. Thanks, Tim. Of course, it's not going to be the same. I think my math teacher would tell me, would remove my diplomas if I say it's going to be the same on an heterogeneous population. But we do expect that it would be consistently positive. And I think that that's what we should be expecting at this point in time.

Thank you. Thank you. Our next question comes from Brian Scorny of Bayard. Your line is open.

Hey, good morning, guys. Thanks for taking the question. Maybe if I could just kind of ask you to characterize some of the areas of the focus for the agency in the mid-cycle review meeting for you. Like who took the most time on the side of the FDA? Was it like the clinical review team, the stats group, the safety group? Is it mostly handed by the lead reviewer, like are Emily Freelich and Teresa Barraccio in the meeting? And I don't know if this is something that comes across in the context of a mid-cycle review meeting, but any insight into FDA's thinking about whether or not they're going to look for DEA scheduling here?

Yeah, so I'll say those meetings are comprehensive. This is not exactly like, oh, they stayed quiet for several months and they come and end up meeting on us. quite the opposites, right? So there's been dialogue and overall it's an opportunity, as you might recall, when Senate with heavy lobby from the industry requested mid-cycle meetings to be implemented as part of a P2 for reauthorization was to actually give us as the applicants an opportunity to have that discussion on how things are going. And I would say very, very little on areas that are of, I would say, interest for people that don't have an interest on this drug getting to the markets like some of your clients. A lot of the interest here was actually how to actually get this drug to help patients. All the errors were represented that you named there as is normally the case. Of course, senior leadership was represented since this is not only I mean, part of the publication, but as one with breakthrough designation. No drug approved mechanistically for essential tremor ever. Only one approved. So you would imagine that that fits exactly the agenda for the FDA from a public health perspective in the United States. And what I would say is, and as we said in the prepared remarks, which, by the way, were legally obliged to be complete, as you know, so I find some of it questions to be honest a little bit annoying is that there was no major like comments here here or there so we see this as as overall incredibly positive uh that we are it's not over yet it's never over uh but one must take at this stage we are right the questions before this call uh were what happens in the mid cycle is the FTA going to have an advisor committee? Is this, this, and that? So maybe it's time to flip the page towards how large of an opportunity essential tremor is and burn the ships, as one say in Carthaga, and start moving forwards, upwards, conquering new worlds.

Thanks, Martin. Our next question, Daniel Brill of Truist. Your line is open.

Hey, guys. This is Alex. I'm for Daniel. Thanks for taking the question. Another question on the mid-cycle reviews. Just given that you have these two mid-cycle reviews in close proximity, any noticeable differences in the tenor, pushback, body language, et cetera, between the FDA reviews for Ulexa versus Rulutrigine? Thanks so much.

I would say... No. On the body language, I think we're all, that is a very collegial discussion throughout the group of the agents and ourselves. And it's amplified by the fact that we are really the only company that probably know every person in that room by name and actually have a trust and rapport with each one of them because there are multiple INGs and multiple NDAs under review. Much, much larger, right, from the... As you can imagine, the application for elixir-cultamide hydrochlorate is so much larger, so there's a lot more people involved on that. But if anything, I'm a paranoid by nature person, so I never expect people to be very happy on meetings like this. But I will venture to say that I think it's very common. As I said, it's very peaceful in body languages. incredibly positive across the board. And it reflects the collaboration throughout the review, as one would expect.

Thank you so much.

Yeah.

Our next question comes from David Hoang of Deutsche Bank. Your line is open.

Hi there. Thanks for the updates and taking my questions. So I want to go back to Olixa's potential commercial launch. Could you talk a little bit about the prescriber base for the drug and remind us if this will be primarily Neuro's writing for it or would a primary care doc, let's say, feel comfortable to write for this drug? And what size of sales force would you need to support a successful launch? And then if you could just remind us of your latest assumptions on peak sales for Alyssa. Thank you.

Sounds good. We'll start with the last part and then I'll hand it over to Megan. The big sales here, I think we've been very conservative on when you look into the size of the opportunities. In general, from number of patients, from not really having anything else. The growth we just mentioned, there have not been adding in general feedback from physicians. You name it, we set that floor into around $10 billion for patients. and I would say the more we move forward, I think the more we feel comfortable that that's really a fairly conservative number. Let me hand over to Megan to discuss the other topics. Yes, absolutely. Thanks, David, for the question.

So from a target perspective, you're right, neurologists are our focus coming out for the launch with us targeting them primarily because of their strong ET influence and just the patient volume. with sort of a call target sizing in the 13,000 to 15,000 range. That puts us in a place of having a field force around 300. And as I shared earlier at the start of the Q&A, we're well underway with our hiring. And again, the context we're heading into with the first targeted therapy, huge unmet need and just the opportunity to have the most successful launch here in neurology, we're definitely attracting top caliber talent that want to be a part of this. So and again, the focus for the build out will allow us to be out in the field doing the account profiling. So we're very well prepared upon PDUFA.

Thank you. Our next question comes from Leonid Timishev of RBCCM. Your line is open.

Hey, guys. Josh on for Leo. Thanks for taking my question. So for the initial patient population that you'll be targeting for relutrigine, are you planning on going after the most severe patients or do you think you'll go more broadly earlier? And how might that play with how clinicians typically may use a novel seizure agent? Thanks.

Yeah, I would say to call any patient with this condition non-severe is probably something I'm never going to be able to do it. The population is the population here, right? Steve represented us into the SCN 2A Family Foundation meeting last week. And we had several updates after that and discussions with them. And many clinicians gave us the feedback based on how they are waiting for this. Some of these hospitals in American Centers of Excellence have, like, very large is either the largest or second largest cohorts of GEs they have. Why we should never be suffering is suffering and we shouldn't compare. But when you look into other GEs that there are three or four companies going after, they are way, way, way less severe and the majority of the patients are being treated there. So we don't see a segmentation per se here, but really careful. I don't think we would want or like everyone to just start right away without doing the proper assessments of these patients without making sure their background medications are optimized before getting into relitrigine. So that is what's going to dictate the launch. I think our medical education exchange discussions are going to focus on proper use because proper use is what leads to maximum penetration and maximum retention and of course maximum benefit for patients and the other parts that we're all interested is maximum revenues that can return to all of us and get more drugs to the market. So that is the strategy here and I couldn't be more pleased to the feedback we're getting from physicians and patient groups.

Thank you. Our next question comes from Rudy Lee of Wolf Research. Your line is open.

Thanks for taking my question. For Ulrich, what gives you confidence that titration can help improve discontinuation in practice?

What data evidence do you have to support your titration proposal, and how should we think about discontinuation rates in the real world? Thanks.

That is a fantastic question and one that we spend a lot of time ourselves and, of course, discussing with the agency. That is why I can't possibly go through every line of evidence here. One thing that is quite key that we haven't, and I'll take full responsibility for not actually discussing this properly publicly before, is if the patient's state, the odds of staying on drug and responding if you just stay a day or two more after arising a tolerability, are disproportionate. So that evidence and the mathematical evidence is very, very clear. So imagine a study, when you conduct today's studies, we wanted to make sure we're not biasing these patients. When a patient goes to an office to discuss with their physician, it's very different conversations, like this is the possible benefits and this is the possible risks, right? but the benefit question is there. In a clinical study, the benefit question is not there. So that is a key driver. So we have a fair bit of data showing that if patients stay on the drug and if they stay a little bit longer, not a lot longer, they're gonna be able to tolerate and get fantastic, in my words, benefits on the other side of that. Our proposal in the label Notwithstanding the fact that the label has to be approved by the agents and so on and so forth, is that physicians are instructed to, if they have concerns, because they know their patients. There are patients that chronically don't respond so well in terms of vulnerability. They can keep the patients for a little bit longer. It is important because they're going to see 70% of the patients doing really well. And then their desire is going to turn into like, I want to get all my patients to do really well. And that's the bridge we want to. What Megan mentioned before about the hub of the future, right? It is really, and we're going to be talking about it on a commercial day coming up soon, going to be announcing, it is really a state-of-the-art way to help the practice manage the patients and getting all the tools to maximize tolerability. We could be here saying, why do we care about those patients, right? It's completely irrelevant from a big revenue perspective, but it's not because we know this drug works and we want to make sure it's there with each one of those patients. So I really appreciate it. It is something very close to our hearts. Our team worked incredibly hard to make sure every percent point is not only a percent point in revenue, it's a lot more patients. They're being able to get benefits that they cannot get any other way. Very helpful. Thanks for the color. Of course.

Our next question comes from Ben Burnett of Wells Fargo. Your line is open.

Hi, good morning, Tim. This is Orfea Zoni for Ben. Congrats on over-enrolling Emerald. I had one question on ReLU and one on your cash runway. First on value, are you able to share what proportion of ML patients are on Excopri or another sodium blockade baseline? And what are your expectations for incremental efficacy in patients who are already on Senebamate? And then secondly, in your cash runway, given that both value and ELSU are eligible for pediatric vouchers, are your current plans to monetize those on approval? And is that contemplated in your cash runway?

Thank you very much.

Yeah. So I think we've got a very representative distribution of what the background meds are here. Very happy. I'll tell you discontinuation, for example, it's a good surrogate. They are being extremely low on this study. Total variability has been very good. We know, and unfortunately, like a lot of these patients, failed pretty much everything. So you name a drug, I'm going to tell you they failed or they are all meds. But we're confident not only on the effects, which is important, but on the safety as well to get to a positive benefit risk. And then I'll leave the last question to Tim, who's been anxiously waiting for a financial question for the call.

Thanks for the question about the runway. And I think part of what we talked about with the runway is it gives us this great opportunity Flexibility and ability to launch into these launches, the way we're investing with Field Force and all the activities that Marcio and Megan have taken us through. With respect to the PRV, because we do anticipate approval for relutrigine for 2A and 8A, where we do have orphan designation and are eligible for a PRV, we would expect to receive that as well. It is not a meaningful impact to our runway, but it does ensure that we can continue to invest in these launches. And you're right also about and Allison Erson down the road because that also has orphan designation. We believe that would be our second product that could be eligible for a PRV. But thank you for the question.

Got it. Thank you. Congrats again.

Thank you. This concludes the question and answer session. I would now like to turn it back to Marcio for closing remarks.

Yeah, thank you so much. I appreciate it. I hope you seem to try to be very comprehensive today, giving updates on... It's just absolutely amazing, palpable energy that we get every single day here in the office with all the now sales team as well and being there and talking to physicians, giving us a lot more of information. I would say as we move this page towards a commercial, a lot of you... helped us along the way to make a successful clinical development for these drugs. As we're going to discuss less and less, the clinical and regulatory, I just want to take a moment to thank all of you, who are certainly my biggest critics and my biggest supporters when we get into certain conversations. And I appreciate every feedback being given to the company made us to where we are right now. Couldn't be prouder on behalf of patients. When we get these stories every single day, and trust me, we get them every single day, from the patients who transition on Emeralds to the Open Label, or the ones who are on Envolves, or the ones who are on Emergency Access of one of our medicines, or particularly these days, for the ones wanting to be on Elixir Calcimides, that's what keeps us going. Thanks. for your support and really looking forward to the conversations later today and in the near future.

Thank you for your participation in today's conference. This does conclude the program and you may now disconnect.