Q2 2026 Praxis Precision Medicines Inc Earnings Call

August 6, 2026

Operator: Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Q2 2026 financial results conference call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. To ask a question, you will need to press star 11 on your phone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to our first speaker today, Daniel Ferry, Managing Director of LifeSci Advisors. Daniel, please go ahead.

Speaker #1: Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines Q2 2026 financial results conference call. At this time, all participants are in a listen-only mode.

Speaker #1: After the speaker's presentation, there will be a question-and-answer session. To ask a question, you will need to press star 11 on your phone. You will then hear an automated message advising that your hand is raised.

Speaker #1: To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to our first speaker today.

Speaker #1: Daniel Ferry, Managing Director of LifeSci Advisors. Daniel, please go ahead.

Speaker #2: Good morning. And welcome to the Praxis Precision Medicines Q2 2026 financial results and business update conference call. This call is being webcast live, and can be accessed on the investor section of praxis's website at www.praxismedicines.com.

Dan Ferry: Good morning. Welcome to the Praxis Precision Medicines Q2 2026 financial results and business update conference call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com. Please note that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, is not taking on an obligation to do so. Please refer to Praxis' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

Speaker #2: Please note that remarks made during this call may contain forward-looking statements within the meaning of the private securities litigation reform act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections.

Speaker #2: While these forward-looking statements represent Praxis's views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking on an obligation to do so. recent filings with the securities and exchange commission for a discussion of certain risks and uncertainties associated with the company's business.

Speaker #2: Please refer to Praxis's most

Dan Ferry: Joining us on today's call are Marcio Souza, President and Chief Executive Officer of Praxis, and Tim Kelly, our Chief Financial Officer. After providing updates on our key programs, we'll move to a brief Q&A session where Marcio and Tim will be joined by Steven Petrou, President of Research & Development, and Megan Sniecinski, Chief Operating Officer. With that, it's my pleasure to turn the call over to Marcio. Marcio?

Speaker #2: Officer. After providing updates on our key programs, we'll move to a brief Q&A session where Marcio and Tim will be joined by Steve Petra, President of Research and Development, and Megan Shininsky, Chief Operating Officer.

Speaker #2: With that, it's my pleasure to turn the call over to Marcio. Marcio?

Speaker #3: Thank you, Dan. Good morning, everyone. Thank you for joining Praxis Q2 2026 conference call. Three months ago, I told you this would be the year Praxis become a commercial company.

Marcio Souza: Thank you, Dan. Good morning, everyone. Thank you for joining Praxis' Q2 2026 conference call. 3 months ago, I told you this would be the year Praxis become a commercial company. This quarter is the one where that stopped being a plan and started materializing into the organization. We have 2 NDAs in late-stage review with the FDA, with both approvals expected in about 6 months. It's extremely exciting to bring both ulixacaltamide to ET patients and relutrigine to SCN2A and SCN8A patients. We have commercial leadership in place, a field force for the first launch hired and trained, and a distribution network established, and inventory being built. I want to spend most of my time today on some key regulatory developments in what we have been building. Let me start with ulixacaltamide.

Speaker #3: This quarter is the one where that stop being a plan and starting materializing into the organization. We have two NDAs in late-stage review with the FTA, with both approvals expected in about six months.

Speaker #3: It's extremely exciting to bring both UX account minds to UT patients and related gene to SCN2A and 8A patients. We have commercial leadership in place, a field force for the first launch hireds, and trained, and a distribution network established and inventory being built.

Speaker #3: I want to spend most of my time today on some key regulatory developments and what we have been building. Let me start with UX account minds.

Speaker #3: Essential tremor affects over 7 million Americans. And there's still no FDA-approved therapy developed specifically to treat the condition. With the potential approval coming up by January next year, UX account minds is poised to change that.

Marcio Souza: Essential tremor affects over 7 million Americans, and there is still no FDA-approved therapy developed specifically to treat the condition. With the potential approval coming up by January next year, ulixacaltamide is poised to change that. 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 agents 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 ulixacaltamide for ET patients.

Speaker #3: Speaking about the NDA review, the FDA completed its mid-cycle communications with us in our very please with the progress and discussions with the agency.

Speaker #3: In that meeting, the agents 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.

Speaker #3: 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 UX account minds for UT patients.

Speaker #3: 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 UT and other neurological conditions.

Marcio Souza: 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 ET 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 Remagine, which would extend the reach of Ulexa further. That work is about expanding the value for patients and Praxis way beyond the initial launch year. Turning to relutrigine. SCN2A and SCN8A are amongst the most severe epilepsies we know of. Seizure onset in infancy, profound developmental delays, and no approved treatment. The addressable population is roughly 10,000 patients in the United States.

Speaker #3: As part of that, you should expect updates from us in the near future about life cycle opportunities for T-type carcinogenic inhibitors, one of those steps is the collaboration with just announced with Reimagine, which would extend the reach of UX further.

Speaker #3: That work is about expanding the value for patients and Praxis way beyond the initial launch year. Turning to related gene, SCN2A and SCN8A are amongst the most severe epilepsies we know of.

Speaker #3: Seizure onset in infancy profound developmental delays, and no approved treatment. The addressable populations roughly 10,000 patients in the United States. As we disclosed last quarter, we submitted additional sensitivity analysis of existing clinical data and the FDA deemed that submission a major amendment.

Marcio Souza: As we disclosed last quarter, we submitted additional sensitive analysis of existing clinical data, and the FDA deemed that submission a major amendment, and the review period was extended with a new PDUFA target now of 27 December this year. In the mid-cycle meeting for relutrigine, very similarly to ulixacaltamide, 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 SCN2A and SCN8A-DEE, and would be eligible for a pediatric review voucher. Just like for Ulexa, launch preparation here is further along than the calendar might suggest. Commercial and medical teams are fully hired, the supply chain is established, and we have built a comprehensive patient support program, all pointing to a very structured and successful launch. The broader opportunity keeps getting clearer.

Speaker #3: And the review period was extended with a new PDUFA target now off December 27 this year. In the mid-cycle meeting for related gene, very similarly to UX account minds, as I just discussed, the agents also confirmed they do not intend to hold an advisory committee meeting.

Speaker #3: If approved, related gene would be the first therapy for SCN2A and 8AD and would be eligible for a pediatric review voucher. Just like for UXA, launch preparation here is further along than the calendar might suggest.

Speaker #3: Commercial and medical teams are fully hired, the supply chain is established, and we have to build a comprehensive patient support program, all pointing to a very structured and successful launch.

Speaker #3: The broader opportunity keeps getting clearer. Enrollment in Emeralds, our studying broadly is, exceeded its target, with approximately 200 patients enrolled spanning more than 50 distinct genetically defined etiology, amongst many others not genetically defined.

Marcio Souza: Enrollment in EMERALD, our study in broad DEEs, exceeded its target with approximately 200 patients enrolled spanning more than 50 distinct genetically defined etiology, amongst many others not genetically defined. That is a trial population that did not exist as a cohort even 5 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 our supplemental NDA approval in 2027. It's also worth mentioning a quick regulatory update that spans both programs. During the quarter, the FDA conducted a BIMO inspection of Praxis as a sponsor for both ulixacaltamide and relutrigine applications. The scope was very comprehensive, including corporate and clinical operation, safety, reporting, data integrity, statistical analysis, and the interim analysis for both programs, amongst other areas of the BIMO program.

Speaker #3: There is a trial population that did not exist as a cohort even five years ago. Assuming they study will be positive and the initial review for related gene in QA and 8A also positive, Emeralds would serve as the base for a supplemental NDA approval in 2027.

Speaker #3: It's also worth mentioning a quick regulatory update that expands both programs. During the quarter, the FDA conducted a BIMO inspection of Praxis as a sponsor for both UX account minds and related gene applications.

Speaker #3: The scope was very comprehensive, including corporates and clinical operations, safety, reporting, data integrity, statistical analysis, and the interim analysis for both programs amongst other areas of the BIMO program.

Speaker #3: 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 of its kind decentralized study for UT, as well as the interim analysis, we're extremely pleased with the outcome of the inspection.

Marcio Souza: We're incredibly pleased that inspections concluded without any findings and therefore, no Form 483 was issued. Considering how complex both programs are with multiple studies and the first of its kind decentralized study for ET, as well as the interim analysis, we're extremely pleased with the outcome of the inspection. One note on how we communicate from now on. Given the stage of discussions on both applications, we do not intend to provide further regulatory updates until the expected action dates. 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 vormatrigine. In June, we reported top-line results from POWER1 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.

Speaker #3: One note on how we communicate from now on. Given the stage of discussions on both applications, we do not intend to provide further regulatory updates until the expected action dates.

Speaker #3: 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 formatter gene in June, we reported top-line results from Power One, and a highly refractory focal onset seizure population.

Speaker #3: As you know, they 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 formatter gene achieving at least 50% reduction in seizure frequency.

Marcio Souza: It did meet a key secondary endpoint with a significantly greater proportion of patients on vormatrigine achieving at least 50% reduction in seizure frequency. That result tells you something specific. 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 miss says 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 POWER2 and POWER3, informed directly by what POWER1 taught us about the dose and entry criteria. We intend to have both studies up and running by the Q4 of this year.

Speaker #3: 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.

Speaker #3: The responder finding says 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.

Speaker #3: Those are design problems, and therefore fixable. We're finalizing the plans to amend and revamp both Power Two and Power Three, informed directly by what Power One 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.

Speaker #3: We will further describe the amendments and impact on the design once they are final in the very near future. Switching gears to health and nursing.

Marcio Souza: We will further describe the amendments and impact on the design once they are final in the very near future. Switching gears to elsunersen. In June, the FDA granted us BTD designation for elsunersen for seizures associated with SCN2A-DEE 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 FDA that the designation gives us. Discussing a comprehensive plan with the agency in the near future. Parallel to that, EMBRAVE3 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. We look forward for a successful rest of the year.

Speaker #3: In June, the FDA granted us BTD designation for health and nursing for seizures associated with SCN2A, DE, caused by gain of function variant. Based on the results of the EMBRAVE Part A study.

Speaker #3: That's our third breakthrough designation since July next last year. Three designations across three different assets on two different platforms. It's basically unheard of for a company like Praxis.

Speaker #3: We're taking advantage of the excess to the FDA that the designation give us and discussing a comprehensive plan with the agents in the near future.

Speaker #3: Parallel to that, EMBRAVE Three 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.

Speaker #3: Let me now turn the call to our CFO, Tim Kelly. Tim?

Marcio Souza: Let me now turn the call to our CFO, Tim Kelly. Tim?

Speaker #2: Thank you, Marceo, and good morning, everybody. Thank you for joining today's call, where you've heard about the good updates that we have going on.

Tim Kelly: Thank you, Marcio, and good morning, everybody. Thank you for joining today's call, where you have heard about the good updates that we have going on. I will provide a quick summary of our Q2 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 Q2, Praxis spent $78 million in operating cash, compared to $55 million in the Q2 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 H2 of this year to support our planned upcoming launches.

Speaker #2: I'll provide a quick summary of our second quarter financials. In Q2, our operating expenses were 96.9 million dollars, with 69.4 million of that for R&D, and the remaining 27.5 million for GNA.

Speaker #2: Which compares to 76 million dollars in operating expenses for the Q2 period in 2025. During the second quarter, Praxis spent 78 million dollars in operating cash, compared to 55 million dollars in the second quarter of 2025, with the increase reflecting greater spend in both R&D and GNA.

Speaker #2: We expect GNA 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.

Tim Kelly: 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 Q2 with $1.4 billion in cash equivalents, and marketable securities, compared to $926 million as of 31 December 2025. We maintain that this is adequate to support our runway into 2028. With that, I will hand the call back over to Marcio.

Speaker #2: We ended the second quarter with 1.4 billion dollars in cash, cash equivalents and marketable securities, compared to 926 million dollars as of December 31st, 2025.

Speaker #2: And we maintain that this is adequate to support our runway into 2028. With that, I will hand the call back over to Marceo.

Speaker #3: Thank you, Tim. Really appreciate it. The updates has now been a move into Q&A operator.

Marcio Souza: Thank you, Tim. Really appreciate it, the updates. Now we are going to move into Q&A. Operator?

Speaker #1: 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 11 on your phone and wait for your name to be announced.

Operator: 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 one one on your phone and wait for your name to be announced. To withdraw your question, please press star one one 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 Yasmeen Rahimi from Piper Sandler. Your line is open.

Speaker #1: To withdraw your question, please press star 11 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.

Speaker #1: Our first question comes from Yasmeen Rahimi from Piper Sandler. Your line is open.

Speaker #4: 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.

Yasmeen Rahimi: Good morning, team. Congrats to an incredible update that I think was very timely and important to us, especially as some bears have been creating some noise around AdCom. 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 relutrigine, 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 ulixacaltamide? Tim, that was really helpful, but if you could dig a little bit deeper around some of the metrics and if you also envision sort of patients have been warehoused as we're getting very close to launch early 2025. Appreciate your color and congrats again.

Speaker #4: You know, APCOM, so thank you for letting us know that you had a successful midcycle 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 literature gene, what is the phenotype of the Salesforce that you have in place?

Speaker #4: What is the size of it, and how do you see the cadence of hiring for a lexicotomide? 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.

Speaker #4: Appreciate your color and congrats again.

Speaker #3: Thanks, Yasa. Absolutely share the sentiment that you just expressed there, right? Like incredibly complex programs, as we discussed on the remarks, to actually shackle the boxes, collaboration with the FCA has been exceptional the real questions we got throughout have really been I would say very straightforwards and really very similar to what we've been discussed before.

Marcio Souza: Thanks, Yas. Absolutely share the sentiment that you just expressed there, right? 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, checked that box quite nicely as well. Of course, the cherry on top is 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 assessment that from data integrity, documentation, communications, procedures, safety of subjects in these studies, everything was checked there.

Speaker #3: Publicly, so we shackled 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're doing everything correctly.

Speaker #3: But that they agree with our assessment that from data integrity, documentation, communications, procedures, safety of subjects in the studies everything was checked there. So we turn a page to talk about what we really talked like talking about that the millions and millions of Americans that are not served currently in the United States.

Marcio Souza: We turn a page to talk about what we really like talking about, 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, team at Praxis. 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. I'll hand over to Megan to discuss a little bit the phenotype and what we are seeing at the stage we are.

Speaker #3: We've been very diligent hiring a world-class sales, marketing, marked access, medical, of course, Tim, at Praxis, and I can say this is probably an opportunity of a lifetime.

Speaker #3: If you are in one of those positions, to launch this drug, to transform patients' lives, but I'll hand over to Megan to discuss a little bit the phenotype and what we are seeing at this stage we are.

Speaker #4: Thanks, Marceo. So yeah, as Marceo was sharing right, not unexpectedly, these are hot launches upcoming. They each represent the first targeted therapies for indications with huge unmet needs.

Megan Sniecinski: Thanks, Marcio. Yeah, as Marcio is sharing, not unexpectedly, these are hot launches upcoming. They each represent the first targeted therapies for indications with huge unmet needs. It's allowed us, from a hiring perspective, to be very selective, and we're incredibly pleased with the caliber of the talent. 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. In the case of relutrigine, now we've got the team hired and trained. We have the next few months to really be active in doing the account profiling, which will set us up quite well from a launch readiness perspective. Then the Ulexa field force build-out's well underway and also on track for where we'll be from a launch perspective.

Speaker #4: 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.

Speaker #4: And in the case of Relucigene, now we've got the team hired and trained, so we have the next few months to really be active in doing the account profiling, which will set us up quite well from a launch readiness perspective.

Speaker #4: And then the Ulexa field forest build is build outs well underway and also on track for where we'll be from a launch perspective.

Speaker #3: Thanks, Megan. Thanks, Yasa, for the question.

Marcio Souza: Thanks, Megan. Thanks, Yael, for the question.

Speaker #1: Thank you. Our next question comes from Ritu Burrell of TD Cowan. Your line is open.

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

Speaker #5: Good morning, guys. Thanks for taking the question. Marceo, I wanted to dig down into your comment about the midcycle the Ulexa midcycle review meeting.

Ritu Baral: Good morning, guys. Thanks for taking the question. Marcio, I wanted to dig down into your comment about the Ulexa 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? 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 Ulexa experience? If I could ask a quick follow-up to that last point, the Ulexa experience, what aspects of commercial launch prep are you preparing to optimize that commercial experience to optimize compliance? Thanks.

Speaker #5: If you'll let me you mentioned the word forward-looking. I guess first, you know could you comment on if there were any surprises during the meeting?

Speaker #5: Any new topics that were unexpected? And two, I guess, you know 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 Ulexa experience?

Speaker #5: And if I could ask a quick follow-up to that last point, the Ulexa experience, what aspects of commercial launch prep are you preparing to optimize that commercial experience to optimize compliance?

Speaker #5: Thanks.

Speaker #3: Yeah. Absolutely. The 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.

Marcio Souza: Yeah. Absolutely. I appreciate the vagueness of what forward-looking might be there. I'll take that one. It was not meant to be vague, was really meant to be what is looking to forward-looking here in the context of this application, right? We are late stage now, approval, labeling, promotion, making sure these patients have access. I think that that's what I meant by that in the conversation. I would say, Ritu, 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.

Speaker #3: 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.

Speaker #3: I think that that's what I meant by that in the conversation. I would say Ritu, the conversation itself in the room there it's the rare type of feeling when you are in a discussion with the FDA, at least in my view, what you actually feel very peaceful.

Speaker #3: 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 being incredibly high and really all the elements that are necessary to make a decision have been on the table.

Marcio Souza: That's the way I would describe how I felt on that discussion where they know for a fact that they're being incredibly transparent, like collaboration's being incredibly high, and really all the elements that are necessary to make a decision have been on the table. On your sub-question about surprise, I would say none, really. Maybe my surprise on the meeting is just how much of the discussions turns into proper use, I would call of the drug. 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? When you are actually marching towards proper use in conversations like this, I consider exceptionally positive the discussions.

Speaker #3: 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 is turned into proper use I'm going to call of the drug.

Speaker #3: 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?

Speaker #3: So when you are actually marching towards proper use, in conversations like this, I consider exceptionally positive the discussions 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.

Marcio Souza: 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. It was good to see that overall. The topic of titration did come up, to your point. That's completely expected. It's something we proposed to have. Once again, I was positively surprised by how much further along our alignment is in that regard.

Speaker #3: And it was good to see that overall. The topic of titration did come up to your point as completely expected, right? It's something we proposed to have and once again, I was positively surprised by how much like further along our alignment is on that regard.

Speaker #3: While I cannot and should not predict what's going to end up saying on a label, I can tell you right now, unequivocally, that that is a very good understanding that when patients start Ulexa Calcimide, they will sometimes in about 30% of the case, have like some tolerability issues that does not transfer to you through safety issues.

Marcio Souza: While I cannot and should not predict what's going to end up saying on a label, I can tell you right now unequivocally that studies have very good understanding that when patients start Ulexa customized. They will sometimes, in about 30% of the case, have some tolerability issues that does not transfer to true safety issues. If they stay on that goes away, and they have this quite phenomenal, in my view, efficacy that is just not there for any other compounds. Any reasonable person, and I think that is 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. I think we're really, really close to figuring that out.

Marcio Souza: While I cannot and should not predict what's going to end up saying on a label, I can tell you right now unequivocally that studies have very good understanding that when patients start Ulexa customized. They will sometimes, in about 30% of the case, have some tolerability issues that does not transfer to true safety issues. If they stay on that, it goes away, and they have this quite phenomenal, in my view, efficacy that is just not there for any other compounds. Any reasonable person, and I think that is 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. I think we're really, really close to figuring that out.

Speaker #3: But if they stay on that, that goes away and they have this quite phenomenal, in my view, right, efficacy that is just not there for any other compounds.

Speaker #3: And any reasonable person and I think the FDA is incredibly reasonable and certainly we believe we are will look into that as an opportunity to maximize the suffering on this incredibly difficult indication.

Speaker #3: By figuring out a way for patients to get there. And I think we're really, really close to figuring that out. How that's translates to commercial and I'm going to hand back to Megan on this as well.

Marcio Souza: How this translates to commercial, I'm going to hand back to Megan on this as well. You can imagine that 70% of the patients on seven million or even two or three million at launch, anyone would say plenty for a very. We want every patient to have the best possible experience, and we want to make sure every patient stay on drug if they desire to and if their physicians believe they should. Maybe Megan can talk a little bit about what we are doing there.

Speaker #3: Right? You can imagine that 70% of the patients on 7 million or even 2 or 3 million at launch anyone would say plenty for a very but we want every patient to have the best possible experience.

Speaker #3: 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.

Speaker #4: Sure. Thanks, Marceo. 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.

Megan Sniecinski: Sure. Thanks, Marcio. 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. As they see the ulixacaltamide 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.

Speaker #4: 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.

Speaker #4: And what they're as they see the Ulexa Calcimide data, right, the ability to tell a patient there's going to be a rapid onset of effect, right, 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 that the patients through that.

Speaker #4: 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.

Megan Sniecinski: 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. 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 on treatment as quick as possible and then titrate through those early weeks. It's absolutely a priority for us, Ritu, and we're feeling really good about where we are with that build.

Speaker #4: 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.

Speaker #4: 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 on treatment as quick as possible and then titrate through that those early weeks.

Speaker #4: So it's absolutely a priority for us, Ritu, and we're feeling really good about where we are with that build. And the excitement and enthusiasm from the physicians is there to get as many patients started on this therapy.

Megan Sniecinski: The excitement and enthusiasm from the physicians is there to get as many patients started on this therapy.

Speaker #1: Thank you.

Ritu Baral: Thank you.

Speaker #2: Thank you. Our next question comes from Francois Brisbois from LifeSci Capital. Your line is open.

Operator: Thank you. Our next question comes from Francois Brisebois from LifeSci Capital. Your line is open.

Operator: Thank you. Our next question comes from François Brisebois from LifeSci Capital. Your line is open.

Speaker #5: Hi. Thanks for the question. So just on Riluchi, Gina, just wondering I think you mentioned that there's about 50 separate genetic ideologies involved here.

Francois Brisebois: All right. Thanks for the question. 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 whatnot?

François Brisebois: All right. Thanks for the question. 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 whatnot?

Speaker #5: Would you say that the study population is relatively enhanced for indications which either have a history of sensitivity to sodium channel blockers or whatnot?

Speaker #3: Yeah. Thanks, Frank, for that. I'll hand over to Steve to discuss a little bit.

Marcio Souza: Yeah. Thanks, Francois, for that. I'll hand over to you, to Steve, to discuss a little bit.

Speaker #6: Yeah. So I mean, you know, looking at the size of the trial, that spread of ideologies is precisely what you would think to get when you look at the distribution of prevalence in that group of patients.

Steven Petrou: Yes. Looking at the size of the trial, that spread of etiologies is precisely what you would think to get when you look at the distribution of prevalence in that group of patients. The precise mix of people that we fully anticipate would be pharmacosensitive to a sodium channel mechanism is represented in that cohort.

Speaker #6: And they're precise mix of people that we fully anticipate would be pharmacosensitive to a sodium channel mechanism is represented in that cohort.

Speaker #5: Okay. Great. And then you mentioned at 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 median percent change that you're looking for for stat seg?

Francois Brisebois: Okay, great. You mentioned at all, can you comment on the powering of EMERALD here? I think based on the study number, is there like a placebo level or a median % change that you're looking for stat sig?

François Brisebois: Okay, great. You mentioned at all, can you comment on the powering of EMERALD here? I think based on the study number, is there like a placebo level or a median % change that you're looking for stat sig?

Speaker #3: Yeah. With the caveat, right, Frank, that a true like multi both genetically diverse, you know, genetic diverse D study has not been run so far.

Marcio Souza: Yeah. With the caveat, Francois, that a true multi, both genetically diverse and non-genetically diverse, GE study has not been run so far. There are many that we can borrow from. When you go through that analysis, I think what we know is there are three levels here. The first, when you look into the overall response, and let's define whatever, 50%, that benchmark is very clear. It's very small for placebo. Of course, these patients are so severe. I'll give you a number. The median baseline countable seizures in EMERALD is over 50 for 28 days. 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 just very, very ridiculously small for placebo.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: Of course, these patients are so severe. I'll give you a number. The median baseline countable seizures in Emerald is over 50 per 28 days.

Speaker #3: So imagine that's kind of burden. And just how little it is, the possibilities that these patients are going to naturally regress, right? The second is as we move upwards the ladder, like 75% response, 90% response, those numbers become like very, very ridiculously small for placebo.

Speaker #3: 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.

Marcio Souza: 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, quite importantly, the a posteriori mix of patients that are pharmacosensitive to the mechanism. Stay tuned soon to come up the results, I think we should be as bullish as we are on what we're going to see on the other end.

Speaker #3: Before you hear from Steve now, we're very pleased not only with the priority powering but quite importantly the a posteriori mix of patients that are pharmacosensitive to the mechanism.

Speaker #3: 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 end.

Francois Brisebois: Great. Thank you very much.

François Brisebois: Great. Thank you very much.

Speaker #5: Great. Thank you very much.

Speaker #2: Thank you.

Operator: Thank you.

Speaker #3: You bet.

Francois Brisebois: You bet.

François Brisebois: You bet.

Speaker #2: Our next question comes from Kevin String of Goldman & Sachs. Your line is open.

Operator: Our next question comes from Kevin Sterling of Goldman Sachs. Your line is open.

Speaker #6: Good morning. I wanted to ask on pharmatogene. You alluded to the design being more important versus the drug itself. Do you mind walking us through sort of the some of the specific learnings from Power One on dose for design that gave you confidence to restart the program?

Kevin Sterling: Good morning. I wanted to ask on vormatrigine, you alluded to the design being more important versus the drug itself. Do you mind walking us through some of the specific learnings from POWER1 on dose or design that gave you confidence to restart the program? Thanks.

Kevin Sterling: Good morning. I wanted to ask on Vormatrigine; you alluded to the design being more important versus the drug itself. Do you mind walking us through some of the specific learnings from POWER1 on dose or design that gave you confidence to restart the program? Thanks.

Speaker #6: Thanks.

Speaker #3: Yeah, absolutely. So we're going to reserve and I hope we don't see this as hedging because it's not. Like 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 detail, and at the same time, keeping ourselves from seeing things that are not there, but really discipline approach to what we're going to do next, right?

Marcio Souza: Absolutely. 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. A couple of things that as we look into in a very detail and at the same time keeping ourselves from seeing things that are not there, it's a 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 four-fifths of the value is on Ulexa and relutrigine. Of course, there's a huge potential for upside and huge residual value for vormatrigine, but we really want to measure that. It's one of the reasons why we're not focused today call on form. Dose clearly played a role. Duration at the dose clearly play a role.

Speaker #3: Looking about the value right now, at least external value for the company, one could argue for 5th of the value is on your Alexa and Riluchi gene, so of course that is a huge potential for upside and huge residual value for vermetrogen, but we really want to measure that as one of the reasons why we're not focused today called on formats.

Speaker #3: Those clearly played a role. Duration at the dose clearly played a role. We sometimes say dose. It looks like it was only the 20 or the 30, but actually 6 weeks and 6 weeks play a role.

Marcio Souza: We sometimes say dose, it looks like it was only the 20 or the 30, but actually 6 weeks and 6 weeks play a role, and I would say a pretty significant role on that. A few other things that you're going to be hearing further, including the number of failures that was extremely high to prior medications that could be tightened up, and a few things here and there. Every single parameter, maybe that's the matter I'm going to leave you with, that we looked into are very easy to adjust and to fix. Then once we do, without overstretching, without drinking the Kool-Aid, without seeing things that are not supposed to be seen there, the effects on the other side for POWER2, and of course, eventually POWER3, are at or higher than what I would expect for this drug on those populations.

Speaker #3: And I would say a pretty significant role on that. I think a few other things that are going to be hearing further including like the number of failures that was extremely high to prior medications that could be tightened up.

Speaker #3: 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 looked into are very easy to adjust and to fix.

Speaker #3: And then once we do, without overstretching, without drinking the Kool-Aid, without like seeing things that are not supposed to be seeing there, the effects on the other side for Power Two and of course eventually Power Three are X or higher than what I would expect for this drug on those populations.

Speaker #3: So great way to look into this. We're finalizing a few things with internally and with our key advisors. You're going to see an update, a fulsome update about that in the near future and restarting of this study.

Marcio Souza: 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 full update about that in the near future, and restarting of this study.

Speaker #2: Thank you. Our next question comes from Tiago Foth of Raymond James. Your line is open.

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

Speaker #7: Great. Thanks for giving the question. Just on Emerald, right? So you know for Dervey, conditional sodium channel blockers are counterindicated sometimes. They can make seizures worse.

Tiago Fauth: Great. Thanks for taking the question. Just on Emerald. For Dravet, conventional sodium channel blockers are contraindicated. Sometimes they can make seizures worse, yet you had really strong preclinical data in Dravet models, right? What does that example tell you about the mechanism relative to conventional sodium channel blockers? 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 DEEs that can be in the mix of Emerald. How should we think about that overall?

Speaker #7: Yet you had really strong preclinical data in Dervey 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 DEs?

Speaker #7: We've been getting a lot of questions on being reached main criteria that you have on seizure burden being enough to offset some of the unknowns or risks from non-ion channel DEs.

Speaker #7: That can be in the mix of Emerald. So how should we think about that overall?

Speaker #3: Yeah. Absolutely. I would start with and then hand over to Steve here at Tiago. The first is I finally ironic. I'm going to say to be the classical me in calls like this.

Marcio Souza: Yeah. Absolutely. I will start with and then hand over to Steve here, Tiago. The first is, I find a little ironic, I'm going to say, to be the classical me in calls like this, that no one asks 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. Maybe one must revisit their own understanding of neurobiology. Having said that, I'll hand over to the person who really knows neurobiology here. That's not me. That's Steve. Steve.

Speaker #3: That no one asks about how many serotonergic mutations are when this is being discussed as serotonergic one, but it's very easy to say sodium channels for us.

Speaker #3: 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.

Speaker #3: So Steve.

Speaker #6: 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.

Steven Petrou: 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. Because of that role, if the sodium channels themselves are altered in their behavior as a result of mutations as we saw in the INVOLVE study, they are a clear target. 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. We've got a lot of confidence that it doesn't really matter what the etiology is.

Speaker #6: And because of that role, they if a sodium channels themselves are altered in their behavior as a result of mutations, as we saw in the involved study, they are a clear target.

Speaker #6: 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.

Speaker #6: Because of that very unique role, they are also targets that where a lot of the physiology converges. So we've got a lot of confidence that it doesn't really matter what the etiology is.

Speaker #6: 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.

Steven Petrou: Even in the cases of loss of function, 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. 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. We're confident of that. Our preclinical data shows that. 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. 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?

Speaker #6: 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.

Speaker #6: So we're confident that a preclinical data shows that the initial 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.

Speaker #6: It's a pretty much crystalline structure of sodium channels and other elements. And that is the little part of the neuron that decides for my experience from everything that's upstream what am I going to do?

Speaker #6: How am I going to respond to that input? And we know that that program is modulated a lot by sodium channel modulation. 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.

Steven Petrou: We know that program is modulated a lot by sodium channel modulation. 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. 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. That was the initial therapeutic hypothesis we started with relutrigine, and we are following that through the trials right now.

Speaker #6: And we know we've talked about this a lot, that the mechanism of action and the profile of Riluchi gene distinguishes itself from any other agent in the market now.

Speaker #6: And that was the initial therapeutic hypothesis. We started with Riluchi gene and we are following that through the trials right now.

Speaker #7: Yeah. Honestly, very helpful. Appreciate it.

Tiago Fauth: Yeah, honestly, very helpful. Appreciate it.

Speaker #2: Thank you. Our next question comes from Douglas Sao of HC Wainwright. Your line is open.

Operator: Thank you. Our next question comes from Douglas Tsao of H.C. Wainwright. Your line is open.

Speaker #8: 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 Two as well as Power Three I'm just curious do you think that those two studies would be enough to support a potential filing?

Douglas Tsao: Hi. Good morning. Thanks for taking the questions, congrats on the progress. I guess, Marcio, I just want to maybe start with vormatrigine for a minute, because it was interesting that you sort of are going to be restarting both POWER2 as well as POWER3. 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 studies in terms of their design and what they're trying to demonstrate. Thank you.

Douglas Tsao: Hi. Good morning. Thanks for taking the questions; congrats on the progress. I guess, Marcio, I just want to maybe start with vormatrigine for a minute, because it was interesting that you sort of are going to be restarting both POWER2 as well as POWER3. 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 studies in terms of their design and what they're trying to demonstrate. Thank you.

Speaker #8: Just given the fact that they are going to be very different studies in terms of their design and what they're trying to demonstrate? Thank you.

Speaker #3: No. Thanks, Doug. Yeah, we do. That's the 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.

Marcio Souza: No, thanks, Doug. 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. 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 the progressive nature of the division that all epilepsy falls within right now as just restructured a couple of weeks ago, I think we feel incredibly bullish about it. To be seen.

Speaker #3: 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 the progressive nature of the division that's all epilepsy falls within right now as just restructured a couple of weeks ago, I think we feel incredibly bullish about it.

Speaker #3: But to be seen.

Speaker #8: Okay. And if I can ask a follow-up in terms of Riluchi gene, I'm just curious because obviously that program or in particular with Emerald is enrolling and there's obviously the efficacy program ongoing as well.

Douglas Tsao: Okay. If I can ask a follow-up in terms of relutrigine. I'm just curious because obviously, that program or in particular with EMERALD, is enrolling and there's obviously the efacimod program ongoing as well. I'm just curious if you have heard any feedback from clinicians, if there's any kind of sort of pattern in terms of what types of patients they're referring to each particular study. Meaning, is there any kind of sort of subconscious enrichment perhaps 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.

Speaker #8: And I'm just curious if you have heard any feedback in terms from clinicians if there's any kind of sort of pattern in terms of what types of patients they're referring to each particular study.

Speaker #8: Meaning is there any kind of sort of sort of subconscious enrichment perhaps ongoing in terms of picking a study in which they think a patient might be best to respond to?

Speaker #8: Just given the different MOAs of the drugs. Thank you.

Speaker #3: No. I get it. And I would say we'll always have to take with a grain of salt anecdotal conversations we have with one or two physicians here and there.

Marcio Souza: No, I get it. I would say we'll always have to take with a grain of salt anecdotal conversations we have with one or two physicians here and there. It is not unexpected, right, that you would say, or no, like, let's say we will start with serotonergics 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 may be okay for a trial execution. It's a terrible strategy once you get to the market, but I'll leave it there. I think likewise for us, the EMERALD trial, as we said, like about 200 patients finished randomization a while back.

Speaker #3: But it is not unexpected right that you would say right now like let's say we will start with serotonergics 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 I would humbly say that yeah that's maybe okay for a trial execution it's a terrible strategy once you got to the market but I'll live it there.

Speaker #3: I think likewise for us the Emerald right as we said like about 200 patients finished randomization like a while back and it is kind of obvious by what is Steve just mentioned that when you look into the final mix that why either by chance or not that this seems to be some of the most potentially like active on this mechanism historically so whether or not there was a conscious or unconscious kind of segmentation when there were sites that were enrolling 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.

Marcio Souza: It is kind of obvious by what Steve just mentioned, that when you look into the final mix that, why either by chance or not, that this seems to be some of the most potentially active on this mechanism historically. Whether or not there was a conscious or unconscious kind of segmentation when there were sites that were enrolling both studies, it happens naturally. You fast-forward a few years from now, both mechanisms work, right? I think we know that. On a market with anywhere between 2 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 incredibly sick kids and young adults to control seizures.

Speaker #3: It's an ability to help 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.

Marcio Souza: Any one of us that thinks that one mechanism is going to do this should be institutionalized. I think it is more than reasonable to expect that multiple mechanisms are going to be. I keep going back to the same thematic. You heard me saying this 1,000 times. I'm going to do 1,001. The zero-sum game idea in genes and epilepsy is purely serving to people who don't want patients to get drugs. Has nothing to do with either drug developments or market potential. If anything else, I'm going to say, I'm going to be cheering every day for Lundbeck to be incredibly successful, just like we're going to be. We all can help patients with these conditions.

Speaker #3: 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.

Speaker #3: You heard me saying there's a thousand times I'm going to do a thousand and one. The zero-sum game idea indeed is an epilepsy is purely serving to people who don't want patients to get drugs has nothing to do with either drug developments or market potential.

Speaker #3: So if anything else I'm going to say I'm going to be cheering every day for Lumbac to be incredibly successful just like you're going to be so we all can help patients with this conditions.

Speaker #8: Okay. Great. Thank you so much, Marcio.

Douglas Tsao: Okay, great. Thank you so much, Marcio.

Speaker #2: Our next question comes from Andrew Sai of Jefferies. Your line is open.

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

Andrew Tsai: 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? If not, can you just remind us what the key steps generally are from here? 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 thought I'd ask. Thank you.

Speaker #8: Hey, team. Good morning. Thanks for all the great set of updates. There's 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 discussion 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?

Speaker #8: Thank you. I appreciate you might not be able to share too much but that's just what I'd ask. Thank you.

Speaker #3: We appreciate it. So the next formal steps here are the quick late cycle discussion I'll tell you that's in the books. Label negotiations that's in the books.

Marcio Souza: I appreciate it. The next forward steps here are the quick late cycle discussion. I would tell you that's in the books. Label negotiations, that's in the books. 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. 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 PDUFA. 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.

Speaker #3: So the reason why we mentioned 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.

Speaker #3: There's a lot of really cool discussions there. We set the goal to be ready for launch a way ahead of the DUFA. For multiple reasons.

Speaker #3: 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.

Marcio Souza: Three, I would challenge absolutely everyone in this call 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. It's just a responsible thing to do. We'll be ready. We are basically ready. We're going to continue to be ready to maximize in the case of the great fortune that the agents finish the review earlier and we are blessed with that approval earlier than the PDUFA.

Speaker #3: Three, I would challenge absolutely everyone in this call to name one market with millions of Americans that don't have a treatment right now that are getting every single day request from physicians and patients to when is this drug going to be available.

Speaker #3: So it's just a responsible thing to do. So we'll be ready. We are basically ready. And you're going to continue to be ready to maximize in the case of the great fortune that the agents finished the review earlier and we are blessed with that approval earlier than the PDUFA.

Speaker #8: Thank you. Fingers crossed. Thank you.

Andrew Tsai: Thank you. Fingers crossed. Thank you.

Speaker #3: Exactly. Thank you. Told as well.

Marcio Souza: Exactly. Thank you. Told as well.

Speaker #2: Our next question comes from Yatin Sunejah of Guggenheim. Your line is now open.

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

Speaker #8: Hey guys. Thank you for taking my questions and again excellent updates today. So just staying with the essential tremor. Could you maybe talk a little bit about the pair work you have done?

Yatin Suneja: Hey, guys. Thank you for taking my questions. Again, excellent updates today. Just staying with the essential tremor, could you maybe talk a little bit about the payer work you have done? I see in the past you have talked about pricing. Love to get the feedback that you are hearing from the payer perspective. In terms of the step edit, how should we think about it? Most people are on generic stuff, they should not be much. Love to sort of understand all of those dynamics. In terms of the commercial build-out, could you maybe outline for us when is that plan in terms of how big of a sales force you would need, all of that stuff? Thank you so much.

Speaker #8: Marci, in the past have talked about pricing, love to get the feedback that you are hearing from the pair perspective. And in terms of the step edit, how should we think about it?

Speaker #8: I mean most people are on generic 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 plan in terms of how big of the sales force you would need?

Speaker #8: All of that stuff. Thank you so much.

Speaker #3: Yeah. Yeah. Absolutely. So from a pair perspective, very, very active. So we did a lot of pre-work to shape like our general understanding. Of course, that is a lot of analytical work that can be done with that.

Marcio Souza: Yeah. Absolutely, Yatin. From a payer perspective, very active. 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 with Don Dads benchmarking work. We moved on the last several weeks to a different phase, right? Where both proactively we want to talk to some of those plan administrators. I would say the latest wave is that they want to talk to us. 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 in the way. The second is just like they want to be ready day one just like we want to be ready day one.

Speaker #3: 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 very 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 in the way.

Speaker #3: The second is just like they want to be ready. They want just like we want to be ready. They want so that's good news.

Marcio Souza: That's good news. Our planning assumptions includes step edits through propranolol. 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 or 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 super bradycardic or something else that it prevents them from ever going into our beta blockers. About half of the market cannot magically take propranolol. One can call that low-hanging fruits, but I guess to call one million patients low-hanging fruits a little bit oxymoronic, I'm not going to do that. That is a very clear part of the market. I think the other parts they just had exposed to that.

Speaker #3: Our planning assumptions includes step edits through propranolol. Not at all by the way what we're hearing across the board is going to happen is just the prudent thing to do.

Speaker #3: Or 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 too bradycardic or something else that it prevents them from ever going into a beta blocker.

Speaker #3: So about half of the market cannot magically take propranolol. One can call that low hanging fruits but I guess to call a million patients low hanging fruits a little bit oxymoronic so I'm not going to do that.

Speaker #3: So that is a very clear part of the market. I think the other parts they just had exposed to that or remind everyone on the stratified predefined use of propranolol on the essential three studies showing that on top of propranolol it looks like I might incredibly efficacious right and so that is really no restrictions here one way or another.

Marcio Souza: I'll remind everyone on the stratified, predefined use of propranolol on the Essential3 study showing that on top of propranolol, ulixacaltamide is incredibly efficacious, right? There is really no restrictions here one way or another. 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. Physicians are incredibly excited about hearing that, which is normally what payers actually want to hear. A lot of work's been done on the payer space. I know you ask 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.

Speaker #3: And welcome. Do we believe that in the long run that's going to be needed to stay on both? 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 wants to hear so a lot of work's been done on the payer space.

Speaker #3: I know you ask 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 to 100,000 per year the there was a lot as you know from clients of yours and from people we talk to you a little bit of pushback and you actually go that high.

Marcio Souza: There was a lot as you know from clients of yours and from people we talk to, a little bit of pushback to 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.

Speaker #3: I think right now while we're not going to disclose the price specifically I think we're actually very constant that that's the right range to operate in general.

Speaker #2: Thank you for your question. Our next question comes from Cam Bees Yazi of US Bancorp BTIG. Your line is open.

Operator: Thank you for your question. Our next question comes from Kambiz Yazdi of US Bancorp BTIG. Your line is open.

Kambiz Yazdi: Morning, team. Thank you for the question. How are you thinking about relutrigine efficacy in EMERALD relative to what was observed in EMBOLD? From a biological level, how should we think about relutrigine performance in broader DEEs compared to the SCN2A-DEE population? Thank you.

Speaker #5: Morning team. Thank you for the question. How are you thinking about the Lutra gene efficacy in Emerald relative to what was observed and involved?

Speaker #5: From a biological level, how should we think about Lutra gene performance in broader DEEs compared to the SCN2A and AA population? Thank you.

Speaker #3: Yeah. So thanks candidates. 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.

Marcio Souza: Yeah. Thanks, Kantez. Good to hear from you. I would start with what is necessary and then what is possible. I think those are two completely different things here. Right. I mentioned earlier in the call, on the background of seizure burden for these patients. Right. 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 we want 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. The bar here is significance on this study. Of course, we want to go above much, much higher than the bar. Right. Bar for success, no doubts whatsoever.

Speaker #3: I mentioned earlier in the call on the background seizure burden for this patients right. Like it is absolutely insane. I cannot even imagine as a parent to have to deal with something like that.

Speaker #3: This patients tries and this parents tries everything they could possibly imagine on those. So logically no matter what he 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.

Speaker #3: So the bar here is significance. On this study. But of course we want to go about much, much higher than the bar right. So bar for success no doubt whatsoever physicians, patients are saying help me control a little bit better.

Marcio Souza: Physicians, patients are saying, Help me control a little bit better. Let me give a little bit more hours without being on top of these kids nonstop, afraid of complications, so 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 he's saying on EMBOLD. I think it's hard to imagine, right, being better than EMBOLD. 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. Again, going to have to stay true to what is possible. Not necessary. Would love nothing more than help these patients to an extreme.

Speaker #3: Let me give a little bit more hours without like being on top of this kid's nonstop afraids of complications so that you name it.

Speaker #3: 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 he's saying on involved.

Speaker #3: I think it's hard to imagine right being better than both but we need to stay true to the science and to what you're seeing so far.

Speaker #3: We're going to discuss a lot more about this in the near future as well but again going to have possible. Not necessary but we love nothing more than help this patients to an extreme.

Speaker #5: Thank you so much.

Kambiz Yazdi: Thank you so much.

Speaker #3: You bet.

Marcio Souza: You bet.

Speaker #2: Our next question comes from Jay Olson of Oppenheimer. Your line is now open.

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

Speaker #6: Oh hey. Congrats on all the progress and thanks for taking our questions. We have another Lutra gene question. And just wanted to follow up on something that you've commented on in the past, Marcia, that you've seen in the pooled mask data from Emerald that you've observed dynamics are profoundly different from what a meta analysis of historic DEE placebo groups could accommodate.

Jay Olson: 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? How would you compare the information in proportion of patients with a 50% reduction versus 75% reduction versus 100% freedom from seizures? Thank you.

Speaker #6: 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?

Speaker #6: Thank you.

Speaker #3: Yeah. No. 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.

Marcio Souza: Yeah. No. Thank you very much. I think that all those parameters you mentioned, right, these continuous of response, 50%, 70%, 75%, 90%, 95%, whatever you want, 100%, are incredibly important. We've been tracking it. 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. Right? Study's been going on for a bit, and we rose relatively fast. There is a very large proportion of patients that have multiple months now in the open label. When you put all of that together, right, the initial responses, 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.

Speaker #3: 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.

Speaker #3: And studies been going on for a bit and we enrolled relatively fast. So there is a very large proportion of patients that have multiple moms now in the open label.

Speaker #3: So when you put all of that together right 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 for the first rock but 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.

Marcio Souza: Hey, who here hasn't been burned by blinded data, right, from the first rock? I'm not saying this is 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 board. We're going to stay vigilant until the end of this study.

Speaker #3: So very happy across the boards but we're going to stay vigilant until the end of this study.

Speaker #6: Super helpful. Thank you.

Jay Olson: Super helpful. Thank you.

Speaker #3: You bet.

Marcio Souza: You bet.

Speaker #2: Our next question comes from Ami Vadia of Needham and Company.

Operator: Our next question comes from Ami Fadia of Needham & Company.

Speaker #7: 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.

Ami Fadia: Hi. Good afternoon. Thank you for taking my question, and congrats on all the positive updates this morning. I had one question on Ulexa and one follow-up on EMERALD. As you think about the uptake of Ulexa, can you talk about the mix of patients that you expect across maybe the commercial Medicare, Medicaid setting? Where do you see the initial patients coming from? Is it sort of older patients that have been suffering with ET for a very long time, or do you also expect younger patients to start to take Ulexa earlier in the launch? With regards to the EMERALD 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 the different etiologies? Thank you.

Speaker #7: As you think about the uptake 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?

Speaker #7: Is it sort of older patients that have been sort of suffering with ET for a very long time or do you also expect younger patients to start to take Alexa earlier in the launch?

Speaker #7: And then with regards to the Emerald study across the 50 etiology 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 the different etiologies?

Speaker #7: Thank you.

Speaker #3: Yeah. No. Absolutely. I mean the so for this launch is going to likely have like several stages right. If you're looking to the I believe we've been quite responsible defining the addressable population at time of launch around 2 million patients and that is mostly I would say three quarters or so of those patients would be the Medicare, Medicare Advantage like arguably is likely older patients there.

Marcio Souza: Yeah, no. Absolutely. This launch is going to likely have several stages. If you look into I believe we're being quite responsible defining the addressable population at time of launch around 2 million patients. That is mostly, I would say three-quarters or so of those patients would be the Medicare/Medicare Advantage, arguably is likely older patients there. Maybe the phenomena that we are seeing more and more is those family members. Right? The interests of those patients. I would say for the phase II, very likely what we're going to see is a migration, continue to increase these patients on the 65 plus. There's a lot of the 40s to 65 patients there. Of course, there's a different payer mix, there's different dynamic on those patients. Maybe the part we don't talk as much about, we kept this number static, but it's not static. Right?

Speaker #3: Maybe the phenomena that we are seeing more and more is though family members right. And the interest of those patients and so I would say for the phase two very likely we're going to see is like a migration continue to increase this patients on the 65 plus but also a lot of the 40s to 65 patients there.

Speaker #3: Of course there's a different payer mix there's different dynamic on those patients maybe the part we don't talk as much about we kept this number static but it's not static right.

Marcio Souza: The population demographics in the United States, and globally, but particularly in the United States, is shifting quite a lot. When you look into the prevalence of essential tremor in the overall population, it's a little bit about 2.5%. When you get to 60s, that is about two and a half times the overall prevalence. About every 10 years after that, it doubles. We haven't discussed, but you're going to hear us discussing a lot more, is actually the completely organic growth of this market that is about double digits. We just don't have drug launches on multi-million patient markets growing organically as a market, double digits, moving forward. That changed a little bit, the mix. I know you had an EMERALD question there as well.

Speaker #3: The population demographics in the United States and globally but particularly in the United States is shifting quite a lot and when you're looking to the prevalence of essential tremor in the overall population it's a little bit about like two, two and a half percent.

Speaker #3: When you get to 60s that is about two and a half times the overall prevalence and then about every 10 years after that it doubles so we haven't discussed but you're going to hear discussing a lot more is actually the completely organic growth of this markets that is about double digits and we just don't have drug launch on multi-million patient markets growing organically as a markets double digits are moving forward.

Speaker #3: So that changed a little bit the mix. I know you had a Emerald question there as well.

Tim Kelly: The efficacy across the etiologies?

Speaker #6: If I see across the etiology.

Marcio Souza: Oh, the efficacy across etiologies. Thanks, Tim. Of course, it's not going to be the same. I think my math teacher would remove my diplomas if I say it's going to be the same on a heterogeneous population. We do expect that would be consistently positive. I think that that's what we should be expecting at this point in time.

Speaker #3: Oh. The efficacy across etiologies. Thanks Tim. Of course it's not going to be the same like I think it would be actually 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 there would be consistently positive and I think that that's what we should be expecting at this point in time.

Speaker #2: Thank you.

Operator: Thank you.

Speaker #7: Thank you.

Ami Fadia: Thank you.

Speaker #2: Our next question comes from Brian Scorney of Baird. Your line is open.

Operator: Our next question comes from Brian Skorney of Baird. Your line is open.

Speaker #5: 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 midcycle review meeting for you Alexa like who took the most time on the side of the FDA?

Brian Skorney: Hey, good morning, guys. Thanks for taking the question. Maybe if I could just ask you to characterize some of the areas of the focus for the agency in the mid-cycle review meeting for you. Who took the most time on the side of the FDA? Was it the clinical review team, the stats group, the safety group? Is it mostly handed by the lead reviewer, like are Emily Freilich and Teresa Buracchio in the meeting? 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?

Speaker #5: Was it like the clinical review team, the stats group, the safety group? Is it mostly handed by the lead reviewer like our Emily Frelich and Theresa Barraccio in the meeting?

Speaker #5: And I don't know if this is something that comes across in a context of a midcycle review meeting but any insight into FDA's thinking about whether or not they're going to look for DEA scheduling here?

Speaker #3: Yeah. So I would say those meetings are comprehensive right. This is not exactly like all they stayed quiet for several months and they come and then the meeting on us quite the opposites right.

Marcio Souza: Yeah. I would say those meetings are comprehensive. Right? This is not exactly like, oh, they stayed quiet for several months and they come and dump a meeting on us. Quite the opposite, right? There has been dialogue. Overall, it is an opportunity. As you might recall, when Senate, with heavy lobby from the industry, requested mid-cycle meetings to be implemented as part of PDUFA for reauthorization, was to actually give us, as the applicants, an opportunity to have that discussion on how things are going. I would say very, very little on areas that are of, I would say, interest for people that do not 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.

Speaker #3: There's been dialogue and overall it's an opportunity as you might recall when Senate with heavy lobby from the industry requested a midcycle 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.

Speaker #3: 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.

Speaker #3: A lot of the interest here was actually how to actually get this drug to help patients all the areas were represented that you named there as normally the case of course senior leadership was represented since this is not only an important application but as one with breakthrough designation no drug approved mechanistically for essential tremor ever only one approved.

Marcio Souza: All the areas were represented that you named there, as is normally the case. Of course, senior leadership was represented since this is not only an important application, but it is one with Breakthrough designation. No drug approved mechanistically for essential tremor ever, only one approved. You would imagine that that fits exactly the agenda from the FDA from a public health perspective in the United States. What I would say is, as we said on the prepared remarks, which, by the way, we are legally obliged to be complete, as you know, I find some of the questions, to be honest, a little bit annoying, is that there was no major comments here, or there. We see this as overall incredibly positive where we are. It is not over yet. It is never over. One must take the stage we are, right?

Speaker #3: 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 on the prepared remarks which by the way were legally obliged to be completes as you know so I find some of the questions to be honest a little bit annoying is that there was no major like comments here or there.

Speaker #3: So we see this as overall incredibly positive that we are. It's not over yet. It's never over. But one must take the stage we are right.

Marcio Souza: The questions before this call were what happens in the mid-cycle? Is the FDA going to have an Advisory Committee? Is this, and that? Maybe it is time to flip the page towards how large of an opportunity essential tremor is, and burn the ships, as one says in Carthage, and start moving forwards towards conquering new worlds. Thanks, Martin.

Speaker #3: The questions before this call were what happened in the midcycle. Is the FDA going to have an advisory committee? Is this this and that?

Speaker #3: So maybe it's time to flip the page towards how large of an opportunity essential tremor is and learn the chips as one say and cart the guts and start moving forwards towards conquering new worlds.

Speaker #6: Thanks Martin.

Speaker #2: Our next. Danielle Brill of Trist. Your line is open.

Operator: Our next from Danielle Brill of Truist Securities. Your line is open.

Speaker #8: Hey guys. This is Alex. I'm for Danielle. Thanks for taking the question. Another question on the midcycle reviews. Just given that you have these two midcycle reviews in close proximity, any noticeable differences in the tenor pushback, body language, etc.

[Analyst] (Truist Securities): Hey, guys. This is Alex. I'm for Danielle. Thanks for taking the question. Another question on the mid-cycle reviews. Just given that you had 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 relutrigine? Thanks so much.

Speaker #8: between the FDA reviews for Ulycsa versus Ralucia Jean? Thanks so much.

Speaker #3: I would say no. On the body language I think we're all that is very collegial discussion throughout the group at the agents and ourselves and exemplified by the fact that we are really the only company that probably know every person on 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.

Marcio Souza: I would say no. On the body language, I think That is very collegial discussion throughout the group at the agents and ourselves, and it's exemplified by the fact that we are really the only company that probably know every person on that room by name and actually have a trust and rapport with each one of them because there are multiple INDs and multiple NDAs under review. Much, much larger, right? As you can imagine, the application for Ulexa calcium hydrochloride is so much larger, so there's a lot more people involved on that. If anything, I'm a paranoid by nature person, so I never expect people to be very happy on meetings like this. I would venture to say that I think it's very calm, as I said, it's very peaceful and body language is incredibly positive across the board.

Speaker #3: Much, much larger right on the as you can imagine the application for Ulycsa might have a chlorate is so much larger. So there is a lot more people involved on that but if anything I'm a paranoid by nature person.

Speaker #3: 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 and body language is incredibly positive.

Speaker #3: Across the board and it reflects the collaboration throughout the review as one would expect.

Marcio Souza: It reflects the collaboration throughout the review, as one would expect.

Speaker #8: Thanks so much.

[Analyst] (Truist Securities): Thanks so much.

Speaker #3: Yeah.

Marcio Souza: Yeah.

Speaker #2: Our next question comes from David Hoing of Deutsche Bank. Your line is open.

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

Speaker #6: Hi there. Thanks for the updates and taking my questions. So I wanted to go back to Ulycsa'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 neuros 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 Ulycsa?

David Hoang: Hi there. Thanks for the updates and taking my questions. I wanted to go back to Ulexa'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 neuros writing for it? Or would a primary care doc, let's say, feel comfortable to write for this drug? What size of sales force would you need to support a successful launch? Then if you could just remind us of your latest assumptions on peak sales for Ulexa. Thank you.

Speaker #6: Thank you.

Marcio Souza: Sounds good. We start with the last part, I hand over to Megan. The big sales here, I think we've been very conservative on when you look into the size of the opportunity. In general, from number of patients, from not really having anything else. The growth we just mentioned, there had not been adding, in general, feedback from physicians. You name it, we set that floor into around $10 billion for 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.

Speaker #3: Sounds good. We start with the last part and I hand over to Megan. The big sales here I think we've been very conservative on when you look into the size of the opportunities.

Speaker #3: In general for a number of patients from not really having anything else the growth we just mentioned there have not been adding in general feedback from physicians.

Speaker #3: You name it we set that floor into around 10 billion for and I would say the more we move forward I think the more we feel comfortable that that's really a fairly conservative number.

Speaker #3: Let me hand over to Megan to discuss the other topics.

Speaker #4: Yep. 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.

Megan Sniecinski: Yep, absolutely. Thanks, David, for the question. 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. 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.

Speaker #4: So 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.

Speaker #4: 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 you John met 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.

Speaker #4: 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 Fedufa.

Megan Sniecinski: Again, the focus for the build-out will allow us to be out in the field doing the account profiling, so we are very well prepared upon PDUFA.

Speaker #2: Thank you. Our next question comes from Leonid Timichev of RBCCM. Your line is open.

Operator: Thank you. Our next question comes from Leonid Timashev of RBCCM. Your line is open.

[Company Representative] (RBC Capital Markets): Hey, guys. Josh on for Leo. Thanks for taking my question. For the initial patient population that you will be targeting for relutrigine, are you planning on going after the most severe patients, or do you think you will go more broadly earlier? How might that play with how clinicians typically may use a novel seizure agent? Thanks.

[Analyst] (RBC Capital Markets): Hey, guys. Josh on for Leo. Thanks for taking my question. For the initial patient population that you will be targeting for relutrigine, are you planning on going after the most severe patients, or do you think you will go more broadly earlier? How might that play with how clinicians typically may use a novel seizure agent? Thanks.

Speaker #5: Hey guys. Josh on for Leo. Thanks for taking my question. So for the initial patient population that you'll be targeting for Ralucia Jean 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?

Speaker #5: Thanks.

Speaker #3: Yeah. I would say to call any patient with this condition non-severe it's probably something I'm never going to be able to do it. So the population is the population here right.

Marcio Souza: Yeah. I would say to call any patient with this condition non-severe, it is probably something I am never going to be able to do it. The population is the population here, right? Ejib represented us into the FamilieSCN2A Foundation meeting last week. We had several updates after that in discussions with them. Many clinicians gave us a feedback, based on how they are waiting for this. Some of these hospitals in America, centers of excellence, have very large, either the largest or second-largest cohorts of DEEs they have. Suffering is suffering, and we should not compare. When you look into other DEEs that there are three or four companies going after, they are way, way less severe, and the majority of the patients are being treated there.

Speaker #3: We are still represented as into the SEN2A family foundation meeting last week. And we had several updates after that and discussions with them and many clinicians gave us the feedback basically on how they are waiting for this some of these hospitals in America centers of excellence have like very large it's either the largest or second largest cohorts of TEs they have.

Speaker #3: 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.

Speaker #3: So we don't see a segmentation per se here but really careful use I don't think we would want or like everyone to just start right away without doing the proper assessments of these patients that are making sure their background medications are optimized before getting into Ralucia Jean so that is what's going to dictate the launch.

Marcio Souza: We don't see a segmentation per se here, but really careful use. I don't think we would want everyone to just start right away without doing the proper assessment of these patients, without making sure their background medications are optimized before getting into relutrigine. 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. 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. That is the strategy here, and I couldn't be more pleased to the feedback we're getting from physicians and the patient groups.

Speaker #3: 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 are all interested is maximum revenues that can returns to all of us and get more drugs to the market.

Speaker #3: So that is the strategy here and I couldn't be more pleased to the feedback we're getting from physicians and the patient groups.

Speaker #2: Thank you. Our next question comes from Rudy Lee of Wolf Research. Your line is open.

Operator: Thank you. Our next question comes from Rudy Li of Wolfe Research. Your line is open.

Rudy Li: Hey, thanks for taking my question. For Ulexa, what gives you confidence that titration can help improve discontinuation in practice? What data evidence you have to support your titration proposal, and how should we think about discontinuation rates in the real world? Thanks.

Speaker #5: Hey. Thanks for taking my question. For Ulycsa so what gives you confidence that titration can help improve this continuation in practice like what data evidence you have to support your titration proposal and how should we think about this continuation rates in the real world?

Speaker #5: Thanks.

Speaker #3: Yeah. No, that is a fantastic question and one that we spent 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 arriving at tolerability are disproportional.

Marcio Souza: That is a fantastic question and one that we spent a lot of time ourselves and, of course, discussing with the agency. While 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 patients stay, the odds of staying on drug and responding, if you just stay a day or two more after arriving at tolerability, are disproportionate, right? That evidence and the mathematical evidence is very, very clear, right? Imagine a study, when we conducted these 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?

Speaker #3: So that evidence and the mathematical evidence is very, very clear right. So when imagine a study when you conduct today's studies we wanted to make sure you're not biasing these patients.

Speaker #3: 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.

Speaker #3: 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 going to be able to tolerate and get a fantastic in my words benefits on the other side of that.

Marcio Souza: The benefit question is there. In a clinical study, the benefit question is not there. That is a key driver. 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 going to 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 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 tolerability. They can keep the patients for a little bit longer. Right? It is important because they're going to see 70% of the patients doing really well.

Speaker #3: Our proposal in the label not standing the fact that 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.

Speaker #3: There are patients that chronically don't respond so well from in terms of tolerability. They can keep the patients for a little bit longer right.

Speaker #3: It is important because they're going to see 70% of the patients doing really well. But 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.

Marcio Souza: Their desire is going to turn into, I want to get all my patients to do really well. That's the bridge we want to. What Megan mentioned before, called the Hub of the Future, right? It is really, and we're going to be talking about in our commercial day, coming up soon, we're 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. It's not, because we know this drug works, and we want to make sure it's there with each one of those patients. I really appreciate it. It is something very close to our hearts.

Speaker #3: What Megan mentioned before about the hub of the future right. It is really and we're going to be talking about in our 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.

Speaker #3: 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.

Speaker #3: 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.

Marcio Souza: 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 that are being able to get benefits that they cannot get any other way.

Speaker #3: It's a lot more patients. They're being able to get benefits that they cannot get any other way.

Speaker #5: Very helpful. Thanks for the color.

Rudy Li: Very helpful. Thanks for the color.

Speaker #3: Of course.

Marcio Souza: Of course.

Speaker #2: Our next question comes from Ben Burnett of Wells Fargo. Your line is open.

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

[Analyst] (Wells Fargo): Hi. Good morning, team. This is Orphea joining for Ben. Congrats on over-enrolling EMERALD. I had one question on RELEW and one on your cash runway. First on RELEW, are you able to share what proportion of EMERALD patients are on XCOPRI or another sodium blocker at baseline? What are your expectations for incremental efficacy in patients who are already on cenobamate? Secondly, on your cash runway, given that both RELEW and ELSYN 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.

Speaker #6: Hi. Good morning, team. This is Orpheus Zone from Ben. Congrats on over enrolling Emerald. I had one question on value and one on your cash runway.

Speaker #6: First on value, are you able to share what proportion of Emerald patients are our next copy or another sodium blocker at baseline? And what are your expectations for incremental efficacy in patients who are already on Sinovimate?

Speaker #6: Then second on your cash runway, given that both value and L2 are eligible for pediatric vouchers, are your current plans to monetize those on approval and is that contemplated in your cash runway?

Speaker #6: Thank you very much.

Speaker #3: Yeah. So I think we got a very representative distribution of all the background meds are here very happy I'll tell you this continuation for example it's a good surrogate they are being extremely low on this study.

Marcio Souza: Yeah. 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 there, being extremely low on this study, tolerability being very good. We know, and it's unfortunately, a lot of these patients failed pretty much everything. You name a drug, I'm going to tell you they failed or they are on it. We're confident on not only on the effect, which is important, but on the safety as well to get to a positive benefit risk. I'll leave the last question to Tim, who's been anxiously waiting for a financial question for the call.

Speaker #3: Tolerability is being very good. We know and it's 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 on it.

Speaker #3: But we're confident so not only on the effects which is important but on the safety as well to get to a positive benefit risk.

Speaker #3: And then I'll leave the last call to the last question to Tim who's being anxiously waiting for a financial question for the call.

Speaker #7: Yeah. 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 flexibility and ability to launch into these launches that the way we're investing with field force and all the activities that Marcio and Megan have taken us through.

Tim Kelly: Yeah. Thanks for the question about the runway. I think part of what we talked about with the runway is it gives us this great flexibility and ability to launch into these launches that 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 an approval for relutrigine for 288a, 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. You're right also about elsunersen down the road because that also has orphan designation. We believe that would be our second product that could be eligible for a PRV. Thank you for the question.

Speaker #7: With respect to the PRB because we do anticipate approval for relutrogene for 2A and 8A where we do have orphan designation and are eligible for a PRB we would expect to receive that as well.

Speaker #7: 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 Elsa Nurson down the road because that also has orphan designation we believe that would be our second product that could be eligible for a PRB.

Speaker #7: But thank you for the question.

[Analyst] (Wells Fargo): Got it. Thank you. Congrats again.

Speaker #6: Got it. Thank you. Congrats again.

Speaker #2: Thank you. This concludes the question and answer session. I would now like to turn it back to Marcio for closing remarks.

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

Speaker #3: Yeah. Thank you so much. I appreciate I hope to see you tonight. It should be very comprehensive today given updates on it's just absolutely amazing palpable energy that we get every single day here in the office.

Marcio Souza: Yeah. Thank you so much. Appreciate. I hope this thing tried to be very comprehensive today, giving updates. 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 this drug that as we're going to discuss less and less, the clinical and regulatory. Just want to take a moment to thank all of you who are certainly my biggest critics and my biggest supporters when we got into certain conversations, and I appreciate every feedback being given to the company made us to where we are right now.

Speaker #3: 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 this drug that we're going to discuss less and less.

Speaker #3: The clinical and regulatory just want to take a moment to thank all of you who 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.

Speaker #3: Couldn't be prouder on behalf of patients when we get these stories every single day and trust me we got in every single day from the patients who transition on Emerald to the open label or the ones who are on bolts or the ones that are on an emergency access of one of our medicines or particularly these days for the ones wanting to be on Lixacutamides that's what keeps us going.

Marcio Souza: Couldn't be prouder on behalf of patients when we get these stories every single day. Trust me, we got them every single day from the patients who transition on EMERALD to the open label, or the ones who are on EMBOLD, or the ones who are on an emergency access of one of our medicines, or particularly these days, for the ones wanting to be on ulixacaltamide. That's what keeps us going. Thanks enormously for your support and really looking forward to the conversations later today and in the near future.

Speaker #3: Thanks enormously for your supports and really looking forward to the conversations later today and in the near future.

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

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