Q2 2025 Praxis Precision Medicines Inc Earnings Call

Dan Ferry: Good day and welcome to the Praxis Precision Medicines Radiant Topline Results and Second Quarter 2025 Financial Results Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to turn the call over to Dan Ferry of LifeStyle Advisors. Please go ahead.

Good day, and welcome to the practice Precision medicines radiant, Topline results. And second quarter, 2025 Financial results conference call at this time, all participants are listening mode.

After the speaker's presentation, there'll be a question and answer session, instructions will be, given at that time.

As a reminder, this call may be recorded.

I would like to turn the call over to Dan Ferry of Life side advisors. Please go ahead.

Tim Kelly: Good morning and welcome to the Praxis Precision Medicines Radiant Topline Results and Second Quarter 2025 Financial Results Conference Call. This call is being webcast live and can be accessed on the investor section of the 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 views in the future. Praxis may update these statements in the future, but 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.

Good morning, and welcome to the Praxis Precision Medicines' Radiant Topline Results and Second Quarter 2025 Financial Results Conference Call.

This call is being webcast live and can be accessed on the investor section of the practice website at www.practice.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, guidelines and financial projections.

While these forward-looking statements represent practices views as of today, they should not be relied upon as representing the company's views in the future.

Practice may update these statements in the future but is not taking on an obligation to do so.

Please refer to practices most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties.

Tim Kelly: Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis, Tim Kelly, Chief Financial Officer, and Steve Petro, Chief Scientific Officer. After our prepared remarks, there will be a brief question and answer session. With that, it's my pleasure to turn the call over to Marcio. Marcio.

Associated with the company's business.

Joining the call today are Marcio De'Souza, president and chief executive officer of Praxis.

Tim Kelly Chief Financial Officer and Steve petrol. Chief scientific officer.

After our prepared remarks, there will be a brief question-and-answer session.

With that.

It's my pleasure to turn the call over to Marcio.

Marcio De'Souza: Good morning, everyone, and welcome to the Radiant Topline Results presentation. We are incredibly excited to share this best-in-disease result with all of you. Before we begin, I would like you to know that today's presentation contains forward-looking statements. For complete disclosures, please refer to our latest FAC filing. Praxis Precision Medicines is in an incredible position to bring innovative drugs to patients with CNS disorders. We have four late-stage assets, one of which we are discussing here today, and we expect five clinical results within the next year. That is no small feat. This progress is powered by our Q-Robust platform, enabling current developments and future CNS drug innovation. Our cash runway extends into 2028, supporting our ambitious clinical agenda.

Marcio.

Good morning everyone and welcome to the radiance. Stop line results presentation.

I am incredibly excited to share the best and disease results with all of you!

Before we begin, I would like to know that today's presentation is contained, forward-looking statements.

For complete disclosures, please refer to our latest FC findings.

Practices in an incredible position to bring Innovative drugs. To patients with CNS disorders. We have 4 late stage assets, 1 of which we are discussing here today.

And we expect five clinical results within the next year.

That is no small fee.

This progress is powered by two robust platforms, enabling clearance developments and future CNS drug innovation.

Our cash runway extends into 2028, supporting our ambitious clinical agenda.

Marcio De'Souza: Today, we will discuss the Radiant results for relutrigine, but it is worth taking a few moments to remind everyone of the rich and deep pipeline we have, with multiple results coming out in the next several quarters, which will enable Praxis Precision Medicines to stay at the forefront of CNS drug development. Focal epilepsy is a very serious medical condition impacting about 3 million U.S. patients. Contrary to common belief, most of the patients are not doing well. Over 60% of those patients require multiple antiseizure medications, highlighting the inadequacy of existing therapies. Patients need effective, tolerable, fast-acting, and durable treatments to avoid the constant ASM cycling, and we believe relutrigine can deliver on that. Starting with today's results, relutrigine is showing best-in-disease efficacy in the Radiant study. That should be enough to be excited.

Today, we'll discuss the radiant results for her gene.

But it's worth taking a few moments to remind everyone of the rich Nizip pipeline. We have.

With multiple results coming out in the next several quarters, which will enable the practice to stay at the forefront of CNS drug development.

focal epilepsy is a very serious medical condition, impacting about 3 million us patience,

Contrary to Common belief. Most of the patients are not doing well.

Over 60% of those patients require multiple anti-seizure medications, highlighting the inadequacy of existing therapies.

Patients need effective. Tolerable, fast acting and durable treatments.

To avoid the constant ASM cycling and we believe our mg can deliver on that.

Is showing back from disease, advocacy in the radiance study.

That should be enough to be excited.

Marcio De'Souza: We should not minimize the further differentiation of relutrigine with current and in development therapies, being the only drug to combine once daily administration, fast action, no food effects, ideal tolerability, and no meaningful drug-drug interaction, which importantly do not interfere with common contraceptive agents. Before I hand over the call to Steve to discuss the details of the Radiant study result, I want to take a step back and talk about execution. We have executed the Radiant study exceptionally well, initially setting an enrollment target of 35 patients with focal epilepsy and 15 with generalized epilepsy. The strong demands for focal, even after we announced the closing of the enrollment through the site, demonstrate the effectiveness of our recruitment capability. The same engine is already at play for the Power 1 and soon to be for the Power 2 and Power 3 studies.

But we should not minimize the further differentiation of our mitragynine therapies, being the only drug to combine once-daily administration, fast action, no food effects, ideal tolerability, and no meaningful drug-drug interactions.

which, importantly, do not interfere with common contrast activation.

Before I hand over the call to Steve to discuss the details of the radian study result.

I want to take a step back and talk about execution.

We have executed the radiance study exceptionally well.

Initially setting an enrollment target of 35 patients with focal epilepsy, and 15 with generalized epilepsy.

The strong demand for Focal, even after we announced the closing of enrollment through the site, demonstrates the effectiveness of our recruitment capabilities.

The same engine is already at play for the power 1 and soon to be for the power 2 and power 3 studies.

Marcio De'Souza: We have so far completed screening of 99 patients and dosed 61 as of July 25th. We expect to complete the study in the near future with approximately 75 patients dosed. Today, we reviewed data from 37 focal patients who completed the study for efficacy so far. We also reviewed the safety for the overall cohort of the 61 patients who have been dosed. We will present more details from this initial cohort of patients at the upcoming International Epilepsy Conference in Lisbon later this month. The full study results are expected to be presented during the American Epilepsy Society Conference later in the year. Let me now hand over the call to Steve to discuss the results. Steve.

We have so far completed screening of 99 patients.

And those 61 as of July 25th.

We expected to complete a study in the near future with approximately 75 patients, dosed.

Today, we reviewed data from 37 focal patients, who completed the a study for Africa so far.

We also reviewed the safety for the overall cohort of the 61 patients who have been dosed.

We will present more details from this initial cohort of patients at the upcoming International Plea Conference in Lisbon later this month. The full study results are expected to be presented during the American Epilepsy Society Conference later in the year.

Let me now hand over to the call to receive to discuss the results.

Steve.

Steve Petro: Thanks, Marcio. Let me walk you through the design of the Radiant study. We began with a 28-day observation period during which patients stayed on their existing antiseizure medications while we monitored seizure activity. Following that, participants received 30 milligrams of relutrigine once daily for eight weeks. An optional two-week safety follow-up was also available at the end of the treatment phase. We're proud to have enrolled a representative sample of the refractory epilepsy population here in the U.S., predominantly female, with a high baseline seizure burden. The median monthly seizure count was 12, and most participants were on multiple antiseizure medications. Looking ahead, we expect the population in our upcoming PRAXIS-1 study to closely reflect what we've seen here in Radiant. That alignment gives us a strong foundation and confidence in how we're approaching the next phase of development.

Thanks Marcia.

Let me walk you through the design of the radian study. We began with the 28th day observation period during which patients stayed on their existing anti-seizure medications while we monitored seizure activity. Following that participants received 30 milligrams of a Metroid once daily for 8 weeks, an optional 2 week safety, follow-up was also available at the end of the treatment phase.

We're proud to have enrolled a representative sample of the refractory epilepsy population here in the U.S., predominantly female, with a high baseline seizure burden. The median monthly seizure count was 12, and most participants were on multiple anti-seizure medications.

Looking ahead, we expect the population in our upcoming Power 1 study to closely reflect what we've seen here in Radiant. That alignment gives us a strong foundation and confidence in how we're approaching the next phase of development.

Steve Petro: Now let's turn to the part that we're most excited about, the results. Relutrigine delivered a truly remarkable performance in the Radiant study. We observed a median seizure reduction of over 56%, and importantly, that effect came on quickly and was sustained throughout the treatment period. Even more compelling, 60% of patients achieved at least a 50% reduction in seizures. That's one of the highest responder rates we've seen in recent epilepsy trials, and it speaks to the potential impact relutrigine could have for this community. What's especially striking is how quickly these responses emerged and how they continued to improve over time. By just week one, 54% of patients had already responded. That number climbed to 67% by week eight, showing a clear and encouraging trend of improvement. Even more notable, over 22% of patients, more than one in five, were completely seizure-free during the second month of treatment.

Now, let's turn to the part of the report we're most excited about: the results.

For Matrouh Gene, delivered a truly remarkable performance in the Radian study. We observed a median seizure reduction of over 56%, and importantly, that effect came on quickly and was sustained throughout the treatment period.

Even more compelling. 60% of patients achieved at least a 50% reduction in seizures. That's 1 of the highest responder rates we've seen in recent epilepsy trials, and it speaks to the potential impact for mitragynine.

What's a specialist striking is how quickly these responses emerged.

How they continued to improve over time.

By just Week 1 54% of patients had already responded that number climbed 67% by week, 8, showing a clear and encouraging trend of improvement.

Steve Petro: That kind of outcome not only underscores relutrigine's potential, but also sets the stage for what we hope to see in the longer 12-week PRAXIS-1 and PRAXIS-2 studies. Looking more closely at the data, relutrigine's efficacy held strong across all patient subgroups, regardless of baseline seizure burden. We specifically analyzed outcomes by splitting patients at the median baseline seizure frequency to explore whether those with a higher or lower seizure load responded differently. As you can see in the figure, the drug performed consistently well across both groups. That kind of robust and uniform response is a strong signal of reliability in a heterogeneous epilepsy population. Taking a step back, it is important to remember what treatments these patients were already receiving when they entered the study. The bar in Radiant was especially high. This was the first epilepsy study launched and reported in the U.S.

Even more notable, over 22% of patients—more than 1 in 5—were completely seizure-free during the second month of treatment.

That kind of outcome not only underscores our maturing potential but also sets the stage for what we hope to see in the longer 12-week Power 1 and Power 2 studies.

Looking more closely at the data for matrices, efficacy held strong across all patient subgroups. Regardless of baseline seizure burden,

Groups that are robust and uniform respond strongly, indicating reliability in a heterogeneous epilepsy population.

Taking a step back, it's important to remember what treatments these patients were already receiving when they entered the study?

Steve Petro: following widespread adoption of cenobamate. In fact, 30% of Radiant participants were already on cenobamate, meaning relutrigine had to demonstrate efficacy on top of an already aggressive background regimen. That context makes the results even more compelling. When we looked at response rates based on the most commonly used background ASMs, the results remained consistently strong. Patients showed excellent responses whether they were on one or more sodium channel blockers, SV2A modulators, or even cenobamate. This level of consistency in both efficacy and tolerability across different treatment backgrounds speaks to relutrigine's versatility. It reinforces the idea that this is a therapy with broad applicability, not limited by the complexity of background regimens. Turning now to safety and tolerability, relutrigine demonstrated a favorable overall profile. Most adverse events were mild to moderate and tended to resolve over time.

The bar in radiant was especially high. This was the first epilepsy study launched and reported in the U.S. following the widespread adoption of Sober, Mate.

In fact, 30% of radiant participants were already on sober, mate. Meaning for Matrix, had to demonstrate efficacy on top of an already aggressive background regimen.

That context makes the results even more compelling.

When we looked at response rates, based on the most commonly used background ASMs, the results remained consistently strong.

patients showed excellent responses whether they were on 1 or more sodium channel blockers, sv2a modulators or even Senova mate

This level of consistency in both efficacy and tolerability across different treatment backgrounds speaks to Volatile's versatility. It reinforces the idea that this is a therapy with broad applicability, not limited by the complexity of background regimens.

Turning now to safety and tolerability.

For matrouh Gene, demonstrated a favorable overall profile.

Steve Petro: We did observe a 23% discontinuation rate, which in many cases was linked to a lack of background ASM dose adjustment despite protocol guidance. Importantly, in six instances where investigators proactively reduced background ASMs, both adverse events and discontinuations were avoided entirely. We see this not as a safety signal related to relutrigine itself, but rather a manageable interaction dynamic that can be addressed with appropriate background therapy management. I will close by saying how proud we are to share these results today. Radiant was a high-bar study in a complex and underserved patient population. We believe the data clearly supports relutrigine's potential to make a real difference for people living with refractory epilepsy. With that, I will now hand the call back to Marcio.

Most Adverse Events were mild to moderate and tender to resolve over time.

We did observe a 23% discontinuation rate, which in many cases was linked to a lack of background. ASM dose adjustment, despite protocol guidance, was important in 6 instances where investigators proactively reduced background ASMs, resulting in both adverse events and discontinuations entirely. We see this not as a safety signal related to veratrole.

I'll close by saying how proud We Are to share these results. Today radiant was a high bar study in a complex and underserved patient population, we believe that data clearly supports the matrouh jeans potential to make a real difference for people living with refractory epilepsy.

With that. I'll now hand the call back to Marcio.

Marcio De'Souza: I'm sure you are as excited as I am about the strength of the Radiant data Steve just reviewed. As we move forward, we must remember that one of the key motivations to conduct Radiant was to better inform the final design of Power 2. In that regard, one of the key aspects Steve did not discuss was the preliminary modeling for dosing and efficacy. We have concluded that it would be beneficial to add a dose arm of 40 milligrams to the Power 2 study, bringing to life the potential of even greater efficacy. We also intend to be more deliberate in our instructions to PI on how to dose-reduce the background ASM for even better management of patients. Another incredibly interesting piece of information we learned in the Radiant study is the reported positive impact in moods observed in patients.

I'm sure you are as excited as I am about the strength of the radiant data itself. Just reviewed.

As we move forwards, we must remember that 1 of the key motivations to conduct Radiance was to better inform the final design of power 2.

In that regard, one of the key aspects that we still did not discuss was the preliminary modeling for those in efficacy.

We have concluded that it would be beneficial to add the adult arm of 40 mg to the power to study.

Bringing to life the potential of even greater efficacy.

We also intend to be more deliberate in our instructions to PEE on how to reduce the background ASM.

For even better management of patients.

Marcio De'Souza: With that in mind, we decided to include a depression and moods endpoint to the Power 2 design. We're ready to start rolling out Power 2, and it goes without saying that the full force of the Praxis Recruitment Engine would be added. The final design of Power 2 enrolled approximately 400 refractory epilepsy patients testing relutrigine doses of 20, 30, or 40 milligrams against placebo over 12 weeks. The enrollment is expected to complete in 2026. I want to now focus the next few minutes into a very important and often neglected part of drug development in epilepsy. As you can see here, we're presenting some data from a very large U.S. claims analysis in patients with focal epilepsy conducted by Praxis, which covers almost half a million patients' worth of data. The message is very clear.

Another incredibly interesting piece of information we learned in the RADIAN study is the reported positive impacts on mood observed in patients.

With that in mind, we decided to include depression and mood endpoints to the Power to Your Design.

We're ready to start rolling out power 2, and it goes without saying that the full force of the practice recruitment engine will be at it.

The final design of Phase 2 in raw, approximately 400 refractory epilepsy patients testing for dosages of 20, 30, or 40 milligrams against placebo over 12 weeks.

The enrollment is expected to complete in 2026.

I want to now, Focus, the next few minutes into a very important and often neglected part of drug development in the plasti.

As you can see here, we're presenting some data from a very large US claims analyst in patients with for for plea, conducted by practice.

Which covers almost half a million patients worth of data.

Marcio De'Souza: The majority of the patients are not doing okay, and virtually two-thirds of them fail their first-line treatment, and after that, a very improvised layering of multiple agents begins. This is not good for patients or the healthcare system. Clearly, there's a critical need for simpler, more effective treatments like relutrigine, ones that combine the fast-acting mechanism with minimum restrictions and high effectiveness. With that in mind, we'll be launching Power 3, which aims to establish relutrigine as standalone therapy, enrolling refractory epilepsy patients transitioning off currently ASM. This study leveraged historical understanding, benchmarks, and safety measures to protect the integrity of the patient and the results of it. We plan to initiate Power 3 in early 2026.

The message is very clear.

The majority of the patients are not doing okay, and virtually two-thirds of them fail their first-line treatments. After that, a very improvised layering of multiple agents began.

Healthcare System.

Clearly, there's a critical need for simpler more effective treatments, like, formatting ones, that combine the fast acting mechanism with minimum restrictions and high effectiveness.

With that in mind, we'll be launching power 3.

Which aims to establish what matters in a standalone therapy? Enrolling refractory plopsy patients transitioning off currently Asm.

This is study leveraged historical understanding benchmarks and safety measures to protect the Integrity of the patients and the results of it.

and we plan to initiate power 3 in early 2026,

Marcio De'Souza: To wrap up the call about relutrigine, it's incredibly exciting to be in the point where we can confidently say it has emerged as best-in-disease ASM, distinguished by rapid seizure reduction, favorable safety, ease of use, and sustained effectiveness across diverse patient groups. The Radiant results significantly bolster our confidence in the ongoing and upcoming studies for relutrigine. Before we move to Q&A and reminding that today's result is about celebrating relutrigine, I want to emphasize that Praxis Precision Medicines remains deeply committed to revolutionize epilepsy treatments, from common focal epilepsy to rare DE conditions. I'm sure you have seen the fantastic news of relutrigine being granted breakthrough designation here in the U.S., which will allow us to move even faster towards registration in patients with SCN2A and SCN8A.

To wrap up the call about 4 mg.

It's incredibly exciting to be the points where we can confidently say it has emerged as best in disease Asm.

Distinguished by rapid seizure reduction, favorable safety of use, and sustained effectiveness across diverse patient groups.

The radiance results significant booster our confidence in the ongoing and upcoming studies program at Virginia.

Before we move to Q&A.

And reminding that today's results are about celebrating Master Jane.

I want to emphasize that the practice remains deeply committed to revolutionizing the policy treatment.

From common focal lapses to rare conditions.

I'm sure have seen the fantastic news of our electrogene being granted breakthrough. Designation here in the US.

which will allow us to move in Faster towards resistance, in patients with scn2a and scn8a

Marcio De'Souza: Lastly, we extend our sincere thanks to our investigators, patients, site staff, and Praxis Precision Medicines team for their contributions to the success of the epilepsy program in overall. We'll now open the call to Q&A. Operator.

Lastly, we extend our sincere, thanks to our investigators. Patience site staff and practice team for the contributions to the success of the epilepsy program. In overall,

We now open the call to Q&A.

Operator.

Dan Ferry: Thank you. If you would like to ask a question, please press star-1-1. If your question has been answered and you would like to remove yourself from the queue, please press star-1-1 again. Our first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.

Thank you, if you'd like to ask a question. Please press star 1, 1 1.

If your question hasn't been answered and you'd like to remove yourself from the queue, please press star, one, one, one again.

Our first question comes from Yasmine Rahimi with Piper Sandler. Your line is open.

Yasmeen Rahimi: Team, congrats really to the outstanding data, both in treatment response as well as seizure-free, especially as the majority of the patients are on background therapies. I guess the first question is, if you looked in terms of the background therapies, were you able to look at if there was a difference in response rate if they were on different products? That is sort of question number one. Question number two is just given the incredible execution into Radiant and you provide a color around Power 2 reading out in, sorry, Power 2 finishing in the back half of 2026. Could you maybe help us understand sort of, I think we get that question a lot. What were sort of the nuggets that lead you to execute really strongly through the study? Then the timing of Power 1.

Team, congrats really on the outstanding data. Both in treatment response as well as seizure-free rates, especially as the majority of the patients are on background therapy.

The first question is, if you looked in terms of the background therapies, were you able to look at if there was a difference in response rate, if they were on different products? That's sort of question number 1. Any question for, uh, number 2 is just given the incredible execution into Radian.

And, and, and, and that, and you provide a color around Power 2 reading out in. Uh, oh sorry, Power 1, Power 2 finishing in the back half of 2026. Could you maybe help us understand, sort of, um,

Yasmeen Rahimi: I think a lot of it sounded like you are on track to finish Power 1 at year end, but if you could just reconfirm guidance around timing of Power 1, that could be very helpful.

You know, I think we get that question a lot. What were sort of the Nuggets that leads you to execute really strongly through the study and then um and then the timing of power 1. I think a lot of it sounded like you're inactive to finish power 1 at your end, but if you could just reconfirm guidance around timing of power 1, that could be very helpful.

Marcio De'Souza: That was great. Thanks, Yaz. Incredibly enthusiastic, right? As we come out here, when you look into focal epilepsy background in general, I think your question is exactly on the specifics. The first question is on the specifics for the background. If you look across Keppra or any of the SV2As, and it's on our slides 13, right? We saw incredibly robust effects on sodium channel blockers in general. Some patients were on one, some patients were on two. You wouldn't expect much of an effect there. I think there was some of the skepticism before, and we're seeing incredibly robust effects as well with over 57% of patients having a response. But maybe the most striking result on that same slide is patients on this study, over 30% of them were on 300 milligrams or even more, sometimes 400, 450 of Cinnobimate.

That was great. Uh, thanks. Yeah, like incredibly enthusiastic right as we come out here. When you look into focal, lapsy background in general, I think your question is exactly on the specifics. The first question is on the specifics for the background to look across, Kera or any of their...

Whois and it's on our slides 13, right? We saw incredibly uh, robust effects on certain channel blockers in general, some patients were once some patients were on 2 uh of like you wouldn't expect much of an effect there. I think there was some of these skepticism before and we seeing incredibly uh, robust effect as well with over 57% of patients, having a response

Marcio De'Souza: This was not your mildly treated, a run-of-the-mill epilepsy patient then. On those patients, we've seen over 55% response. So if there is any doubt on the placements in terms of refractory, I think that should be no more. We did talk as well on what we believe to be the proper way for this drug to be used. It's really moving towards first therapy and first line, and that's why we're starting the Power 3 study, but I'm sure we can discuss that soon. So going back to your question, right? We set up to recruit a smaller group of patients, and we end up recruiting. That should be a big checkmark on our ability to recruit this population that, as you've seen on the demographics slide, is your classical refractory, seizing a lot of multi-treated patient population in the United States and in Europe.

Expands in terms of refractory, uh, I think that should be no more. Uh, we did talk as well on what we believe to be the proper way for this drug to be used is really moving towards first, uh, therapy and first line. And and that's why we're starting the power 3, uh, study. But I'm sure we can discuss that, uh, soon. So, going back to your, to your question, right? We set up.

Marcio De'Souza: So I'm pretty happy with that. Not happy for the patients on being treated with those drugs, but happy on the fact that we can recruit them well. That is already happening on Power 1, the acceleration. We did in our corporate release in our form 10Q, which should be filed right now, and you can refer to, reinforce the guidance that we previously gave on finalizing Power 1 this year. Power 2 is not off the ground yet, so one should always be careful on making predictions of studies that have not started. But based on our engine, particularly here in the U.S., we're really able to get high-quality sites and to help the sites with their own recruitment efforts, with our own recruitment efforts to get more patients.

To recruit a smaller uh group of patients and we end up recruiting. Uh that should be a big check mark on our ability to recruit this population. As you've seen on the demographics slide as as your classical refractory uh seizing a lot uh multi-reedist.

Marcio De'Souza: We believe more patients in a site is a good thing because then they have more experience, the quality is higher, the overall operations run smoother. That is going incredibly well. We are going to transfer that enthusiasm towards Power 2 and pretty soon in the future, Power 3 as well. It is on and off. It is not only a phenomenal result as we see for patients today, but in general, it brings us a step closer or an inch closer to completing Power 1 and to getting Power 3 and getting that registrational. It is particularly sad as others struggle here to recruit on the same population, and one must ask why. But on our case, we are incredibly happy with our execution and our team's focus on getting these patients on these studies.

Studies that have not started. But based on our engine particularly here in the US what are really able to get high quality sites and to help the sites, uh, with their own recruitment efforts, uh, with our own recruitment efforts to get more patients, we believe more patients in our site is a good thing because then they have more experience. The quality is higher. The overall operations runs smoother. Uh, so that is going, uh, incredibly well. Uh, so we're going to transfer that enthusiasm towards power 2 and, uh, pretty soon in the future power 3, as well. So it's on and off. It's not only a phenomenal result as we see for patients today. Uh, but in general, it brings us a step closer or a ninch closer to, uh, completing power 1 and to getting power 3 and, and getting that registration of uh uh it's particularly sad as others is.

Struggle here to recruit on the same population and one must ask why. Uh, but in our case, we are incredibly happy with our execution and our team’s focus on getting these patients on these studies.

Yasmeen Rahimi: Thank you so much. Congrats again.

Marcio De'Souza: Of course.

Thank you so much. Congrats again.

Of course.

Dan Ferry: Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open.

Thank you. Our next question comes from Reuber Al with TD Cowen. Your line is open.

Ritu Baral: Hey, guys. Good morning and congratulations on this really, really good data. I have gotten a bunch of questions this morning just being driven by this 22% seizure-free rate and this sort of large percentage of patients that responded very rapidly. Marcio Souza and Steve, what do you think is driving this increase in efficacy on all these measures? Excuse me, even after steady-state plasma is achieved in patients, and do you have any exposure response analysis done which is contributing to the 20 milligram dose that you now plan on including in Power 2? Then I have got just a quick housekeeping follow-up. Thanks.

Hi guys. Good morning and uh, congratulations on this. Um on this really, really good data. I I've gotten a bunch of questions this morning just um being driven by this 22%, um, seizure free rate, um and this sort of um large percentage of patients that responded, very rapidly. Um,

Marcy and Steve. What do you think is driving these this increase in efficacy? Um, on on all these measures?

Even after.

steady state plasma is achieved, um,

Marcio De'Souza: Yeah. No, thank you so much, Ritu. We do have the exposures, and I would say the raw exposures are already quite well processed, and the preliminary exposure response is well underway as well. I will make a couple of comments about that, and then I will hand over to Steve to talk about why we were expecting and we were seeing these phenomenal results. We do see steady state being reached quite quickly here between the first and the second week of treatment. As you have seen on these slides, off the gate to get very good results. It dipped quite considerably. We thought the most scientifically relevant way to present was actually fitting the lowest to the charts because we know epilepsy is not a weekly process, right?

In a patients. And um, is your do you have any exposure response analysis done which is contributing to the 20 mg dose that you now plan on, including in power 2? And then I've got just a quick housekeeping follow-up. Thanks.

Yeah.

No, thank you so much for that. So we do have the exposures, and I would say that the raw exposures are ready quite well.

Process. And the preliminary exposure response, uh, well, on their way as well. So I'll make a couple comments about that. And then I'll hand over to Steve to talk about why we are we were expecting. And we are seeing this, uh, phenomenal results. So, we do see a steady state being reached quite quickly, uh, here between the first and the second week, uh, of of treatments

As you've seen on these slides, uh, of the gate to get very good results. It deepens quite considerably. Uh, we, we fought the most, uh, scientifically relevant way to present was actually feeding the lowest

Marcio De'Souza: The patients do not seize otherwise. We will observe them for a week and then just treat for a week or two afterwards. It is the overall month, I think, the metric here. We do see less. I think the overall concept is that less seizures leads to less seizures. So you see this dipping over time, which bodes incredibly well for Power 1, which is 12 weeks long, and Power 2 is going to be 12 weeks long as well in that regard. The 20 milligram dose that we are using for the first six weeks of Power 1 is rising to the range where you are seeing this incredible efficacy, clearly the 30 as well.

Leads to last Caesars. So we see this dipping over time which balls incredibly well for power 1 which 12 weeks long.

Marcio De'Souza: But what you are seeing is a potential for a fairly significantly higher when you go to the much higher sides of the exposure on these patients to get an even bigger result here. Not that we need it. This is the highest seizure reduction ever seen on an epilepsy study. Not that we need any more, but I think these patients deserve more, and we are going to drive that. That is why we added the 40 milligrams. So in a sense, it is going to be stepping into Power 2, expecting all three doses to be quite effective and giving this flexibility for the patients. But maybe Steve can talk about why we think the dipping is granted.

Steve Petro: Yeah, it just speaks to the issue you raised, Marcio, about fuel seizures causing fuel seizures. The same thing, the old saying in epilepsy is seizures beget seizures, and that's a process of really resetting the activity level of a neuron. That's a molecular process that takes time to occur. Conversely, when you give an agent like relutrigine, vormatrigine, you immediately decrease activity, and that's actually starting to reset the level of neuronal activity. So that process takes time to unwind as it took time to wind up. We just think it's really the opposite corollary of increasing seizures as a patient first presents. There are well-known physiological mechanisms, homeostatic plasticity, etc., that are known to underlie this phenomenon.

And power 2 is going to be 12 weeks long as well. Uh, on that regard, the 20 Mig dose, uh, that we are using for the first 6 weeks of power. 1 is rising to the range or you are seeing this incredible efficacy, clearly the 30 as well. But what you've seen is a potential for a fairly significantly higher when you go to the to much higher sides of the exposure of this patience uh to get an even bigger results, here. Not that we need it. Not like uh this is the highest seizure reduction uh, ever seen on an epilepsy study, uh not that we need anymore. But I think these patients do deserve more and we're going to drive that and that's why we added the 40 mg. So in a sense it's good to be stepping in into Power 2, expect all 3 of those to be quite effective and uh, giving this flexibility for the patients, but maybe Steve can talk about why we think the deepening is. Granted. Yeah, I just

Speak to the issue. You raised about your about Siege fuel, seizures causing fuel seizures, and the same thing at the old saying in epilepsy. See, just beget seizures, and that's a process of re really resetting. Um, the, the activity level of a neuron that's in molecular process that takes time to occur conversely. And when you give an agent,

Like religion with a mitragynine, you immediately decrease activity and that that's actually starting to reset the level of neuronal activity. So that process takes time to unwind as it took time to wind up. So we just think it's really the opposite corally of increasing seizures as as a patient, uh, first presents and there's well known physiological, mechanisms homeostatic, plasticity Etc, um, that are known to underly this phenomenon.

Ritu Baral: Super helpful. Marcio, you knew this was coming. The upcoming Power 1 data, you mentioned you would finish enrollment and have data by end of year. Is there any more granularity that you can give us around where enrollment currently stands? Will you announce completion of enrollment for that study?

Marcio De'Souza: Yeah, we probably will announce the completion. I would say at this point today is the day to celebrate Radiant. Yes, I could see this coming. I appreciate you professing with that. The enrollment is incredibly strong. I just had a call this morning with most investigators, and the enthusiasm of everyone that is on Power 1 is really great to see. I know it was in these slides, and I reinforce it. One of the things on Radiant that we were not expecting was really this overwhelming feedback from patients and investigators on their improvements in moods, on their ability to cope better with their day. I think investigators like that a lot as well, and that is certainly helping with even more patients being funneled towards this study versus other things going on out there.

Super helpful and then Marcio, you knew this was coming. Um the upcoming power 1 data. You you mentioned you would finish enrollment and and have data by end of year. Is there any more granularity that you can give us around where enrollment currently stands. Um and will you announce uh completion of enrollment for that study?

Yeah. Well, we, we probably will, uh, announced the completion. Uh, and I would say at this point today is the day to celebrate, uh, radio. But I, yes, I could see this coming. I appreciate you. You're professing with that. The the, uh, enrollment is incredibly strong. Uh, uh, we just had a call this morning with most investigators and the enthusiasm of everyone that is on power. 1 is is really great to see. Um, I know it was in these lives and and I reinforced it but the the

1 of the things on Radiance that we're not expecting. Uh, was really this overwhelming feedback from patients and and investigators on their improvements in moods, on their ability to call better with their day. And I think investigators like that a lot as well. And and that is certainly helping with even more patients being uh, funnel towards this study versus uh, other things going on out there.

Ritu Baral: Great. I will hop back in the queue. Thanks.

Great. Uh,

Marcio De'Souza: Thanks.

thanks.

Dan Ferry: Thank you. Our next question comes from Joon Lee with Truist Securities. Your line is open.

Thank you. Our next question comes from June Lee with truist Securities. Your line is open.

Joon Lee: Hey, guys. Congrats on the data, and thanks for taking our questions. Can you elaborate a little bit more on the discontinuation rates in the Radiant and how that was inputted into the seizure reduction data, if at all? Also, for the forthcoming Power 1, would it be fair to assume that placebo rates will be lower than those reported for Cinnobimate and Xenons, a drug given the more refractory populations in Power 1? Thank you.

Marcio De'Souza: Yeah, no, thanks. Thanks, Joe. So why we are, we think we can do better on the discontinuation, right? If you look into comparatively our other studies, it is fairly similar, as I am sure you already done the comparison in overall. So not quite completely satisfied there yet because we have seen what happens when investigators actually follow the pellets they had on the protocol. It does not happen, right? Or it happens at a very low rate. I think that is what we are going to see moving forward. Having talked with some of them already over the weekend and so on, I think some regrets they would not have removed some of the drug. So not as much on the impact, to your question, on the ability to reduce seizures, but just that is a lot on top of these patients.

Hey guys, congrats on the data and thanks for taking our questions. Um, can you elaborate a little bit more on The discus discontinuation, uh, rates in the radian? And how that was imputed uh into the seizure reduction, uh data if at all and also for the forthcoming power 1, would it be fair to assume the placebo rates will be lower than those reported for so Noble maidens? You know, and a drug given the more refractory population, uh, in part 1. Thank you.

Yeah, no thanks. Thanks, Joe. The so why we are uh, we think we can do better on this discussion, right? Like if you look into comparatively or other studies, it's fairly similar, uh, as I'm sure you already done. The, the comparison uh, in overall so not quite completely

Satisfied. Uh, there yet because we've seen what happens when investigators. Like actually follow the uh billets they had on the protocol the uh it doesn't happen, right? Or it happens at a very low rate and I think that's what we're going to see moving forwards.

Marcio De'Souza: I think that that is what is leading primarily here for patients not wanting to stay. It was also an easy study to come out as well, right? When you are in the open-label setting, it is certainly more reports of side effects in general and easier to discontinue. So I am not completely surprised. It was a little bit higher than we expected, but it is still lower than Cinnobimate compared to other drugs in the market with lower efficacy. You mentioned what we should be expecting for Power 1. I agree, in general, what you are seeing this patient population has two things, right? So one is the background, as you mentioned, very difficult, very refractory in general. The second is really the quality of the sites, the quality of the patients that are coming in, the stability of these patients on their seizures beforehand.

The drug. Uh, so not as much on the impacts, uh, to your question on the ability to reduce seizures, uh, but just that is a lot on top, uh, of these patients. And I think that that's what is leading, uh, primarily here for patients, not want to stay because that's what needs to study to come out as well, right? When you, uh, when you are, uh, in the open label setting. Uh, it's certainly more reports of side effects in general and easier to to discontinue. So I'm not completely surprised. Those are a little bit higher, uh, than we expected, but it's still lower than Sonoma.

Comparative to other drugs in the market with lower efficacy.

Oh, and and you mentioned, what we should be expecting for for power 1? I agree. Uh,

Marcio De'Souza: So I think when you get a higher number of patients per site, higher quality of assessment, good level of stability in terms of the seizures beforehand, that all contributes to lower potential placebo rates.

On in general, the what you're seeing this patient population at 2 things, right? So 1 is the background, as you mentioned, very difficult, very refractory, uh, in general. And then the second is really the quality of the sides. The quality of the patients are coming in. They stability of these patients on their seizures beforehand. Uh, so I think when you get like higher number of patients per sides, higher quality, uh, of assessment, good level of stability, in terms of the seizures. Uh, beforehand, that's all contributes to to lower, uh, potential placebo.

Rates.

Joon Lee: Thanks, guys.

Marcio De'Souza: Of course.

Thanks guys.

Of course.

Dan Ferry: Thank you. Our next question comes from Douglas Tsao with H.C. Wainwright. Your line is open.

Thank you. Our next question. Comes from Douglas s with HC Wayne Wright. Your line is open.

Joon Lee: Hi. Good morning, and congrats on the data. I guess as a starting point, in terms of the added effect of increasing efficacy that we see over time, that was something that we saw with relutrigine as well. I am just curious, the two molecules are similar in many respects. Do you think that that is a function of sort of how they interact with the sodium channel uniquely that you sort of get this decandling effect, which I think Steve sort of talked to, I think, in response to Ritu's question? Then I have a question.

Hi, good morning and congrats on the data. Um, I guess this is starting point, you know, in terms of, you know, the added effect of the increasing efficacy that we see over time, um, that was something that we saw with the Lucha Gene as well. And I'm just curious. Um, you know, the 2 molecules are, are, you know, similar in many respects. Um, do you think that that is a function of sort of how they interact with the Sodium Channel uniquely that you sort of get this detangling effect, which, you know, sort of, I think Steve sort of talked to um, I think in response to reach these questions.

Steve Petro: Yeah, maybe just to further what I said before, Doug. That's very specific and different to how any other molecule interacts with the sodium channel, their biophysical profile. We think that's got a lot to do with this effect because they target the activity more than they target normal function. They target the epileptic activity. I think that profile leads to this rapid and then this growing because we're having such good acute efficacy, and that encourages this longer-term efficacy to grow over time. So very much associated with their biophysical character.

and then I have a

Yeah, maybe just to further what I said before. Doug the yeah, that's very specific and different to how any other molecule interacts with the Sodium Channel there biophysical profile. And we think that's got a lot to do with this effect because they target the activity, um, more than they target normal functions, they target the epileptic activity within that, that profile leads, um, to, uh, this rapid. And then this growing because we're having such good acute efficacy and that, that that encourages these longer term efficacy to grow over time. So very much associated with with their bio physical character.

Joon Lee: Okay, great. And I guess on the side effect profile, I am just curious, Marcio or Steve, to the extent that you have been able to sort of detangle the effect that some of these side effects were or AEEs were related to relutrigine versus the background therapy. And as you look to the power studies, sort of thinking about enabling some sort of reduction in dosing in background ASMs, which obviously probably contributes to many of the side effects experienced by patients.

Marcio De'Souza: Yes, absolutely right. But maybe before there, I will ground us on the table on our slides 23. The vormatrigene treatment emerging AEs is over 20% lower than any other drug out there, 20% less patients. But if you are talking about any other therapeutic area, this is like 100 miles from anything else. On CNS-related, it is about 20% as well. So we are already in another, like, universe when it comes to these other drugs that are unfortunately in the background, right? We cannot disentangle what these other things are doing, but what we know, because we ran the experiments, is it gets reduced or removed when the background drugs are reduced, which ultimately is what these patients do, and what the physicians do.

Okay, great. And I guess on the side effect profile I'm just curious Marcio or Steve or, you know, to the extent that you've been able to sort of detangle the effect that some of these side effects were or AES, um, were related to format Gene versus the background therapy. Um, and you know, as you look to the power, um, you know, the power studies, um, you know, sort of thinking about enabling some sort of reduction in dosing in, in background asms, which, you know, obviously probably contribute to the to to, to many of the side effects experienced by patients.

Yeah so so ah ah absolutely right but maybe a before there are all ground us on the table on our slides 23. All right, the

For messaging, treatment emerging a is this over 20% lower than any other drug out there. 20% less patience, but if you're talking about any other therapeutic area, this is like a 100 miles from anything else on CNS related, it's about 20% as well. So, we already in the other like Universe when it comes to to this other drugs that are unfortunately, in the background, right? So we, we can't disentangle what these other things are are doing. But what, we know because we we ran the experiments is

Marcio De'Souza: So we see that as incredibly positive, not only for patients continuing on Radiant since we have a significant more now and for open-label extension as well, but for the Power 1 and Power 2 and potentially Power 3 studies as well. Yes, I think the trajectory, while we should ground on the numbers and be happy about being best in class and here in best in disease, that is a space to get better. That is where we are moving forward.

It gets reduced or removed when the background drugs are are reduced, which ultimately is what is patients do, right? And what the Physicians do. So we see that it's incredibly positive. Not only for patients, continuing Radiance, since we have a significant more now and more open label uh extension as well.

I studies as well so so yeah I think the trajectory while we should ground on the numbers and and be happy about being Best in Class and here investing disease. Uh that is a space to to get better. That's why we're moving forward.

Joon Lee: Okay. If I can one follow-up, I am just curious on the mood benefits that you saw. I am just curious, was that based on anecdotal feedback, or was there any kind of inventory on emotional state taken?

Marcio De'Souza: Yeah. So it was fairly systematically reported by sites, but unfortunately, we had not designed an instrument to collect that from the very beginning. That is where we are incorporating on the Power 2 design. It is not completely unexpected, right? I think there are other drugs in this class that have approval for bipolar, for example, like vormatrigine, but they just cannot be used broadly because of the other issues, including like the allergic reactions to the drug. So again, not completely unexpected, but it was a very welcome comment that we got across the board from investigators.

Okay, and if I can 1 follow up, um, I'm just curious on the mood benefits that you saw. I'm just curious, was that based on sort of anecdotal feedback, or was there any kind of um, um, sort of uh, inventory on emotional stake in?

Joon Lee: Okay, great. I'll hop out of the queue. Thank you.

Yeah, so you will start a systematically, uh, reported by sites. Uh, but unfortunately, we have not designed, uh, an instruments to collect that from the very beginning, and that's where we are incorporating. All the power to, uh, design, ah, ah, it's not completely unexpected, right? I think there's other drugs in this class that have, uh, approval for bipolar. For example, like well motor Gene, uh, but they just can't be used properly because of the other issues, including like the allergic reactions to, to the drugs. So not again, not completely unexpected, but you was a very welcome comments that we got uh, across the board from investigators.

Okay, great. I'll hop that over to you. Thank you.

Dan Ferry: Thank you. Our next question comes from Yatin Suneja with Guggenheim. Your line is open.

Thanks.

Douglas Tsao: Hey, guys. Thank you for taking my question, and let me add my congratulations. Very nice results. Again, congratulations to the team. A couple for me. The first one is, could you talk about the kinetics of responses in the sense that are you seeing improvement in efficacy over time for most patients? When you do a 12-week study, you probably get more benefit. The reason I ask is because I couldn't really figure out from the chart that you have, are you seeing sort of deepening of this efficacy throughout the period? That's first. The second one is, what should be the read-through to generalized data that you will have for the same asset? What should be the expectation there?

Thank you. Our next question comes from Yacht and Essay with Guggenheim. Your line is open.

Douglas Tsao: Finally, on the safety, which I'll ask, I mean, you should be very comfortable with the safety, especially the tolerability if you are going with the 40 milligram in the future study. Those are the three questions. Thank you.

Hey guys, thank you for taking my question, and let me add my congratulations. Very nice results. Um, again, congratulations to the team. So, a couple for me. Um, so the first one is: could you talk about the kinetics of responses, um, in the sense that are you seeing improvement in efficacy over time for most patients? And then, when you do a 12-week study, you probably get more benefit. And the reason I ask is because I couldn't really figure it out from, um, the chart that you have. Are you seeing with deepening of this efficacy throughout the period? So that's the first. Second one is, um, you know, what should be the read-through to generalized data that you will have for the same asset? Uh, what should be the expectation there?

Marcio De'Souza: Yeah. No, thanks, Yaz. On the kinetics of the response, it is very clear. We thought it would be disingenuous to just get a straight line there to fit like a linear. But if that was the case, and you can do it yourself since the data, you would see it's a very significant dipping between the first month and the second month, which we expect to continue as we treat this patient further. So for Power 1, the translation should be an even deeper response there. Of course, we are going to have to wait for that study to read out, but that is the expectation based on the data we have. That is kind of the read-through that was the second part of your question.

And then finally uh, on the safety, which I'll ask uh I mean you should be very comfortable with the safety especially the tolerability if you are going with the 40 migram in the uh in the future study. So yeah those are the 3 questions. Thank you.

Yeah.

No, thanks. Yeah, the, the on the kinetics of the um,

Marcio De'Souza: When you look into safety, as we are very comfortable going to 40 milligrams, we really see this association being a lot more related to the time and type of management by the investigators than the drug itself. We do see, as I mentioned in one of the previous questions, on the higher end of the exposure response, we see even further efficacy response or deepening. So when you combine that with another month of treatment, we should expect significantly better results here. Once again, not that it's needed, right? This is already the best result in an epilepsy study.

Of the response, it is very clear, like we thought it would be. This ingenious approach to just get a straight line there to fit, like a linear one. Uh, but if that was the case, and you can do it yourself since the data, uh, you would see it's a very significant difference between the first month and the second month, which we expect to continue as we treat this patient further. So for power one, the translation should be, uh, even deeper, uh, response. There, of course, going to have to wait for that, uh, study to read out, but that is the expectation based on the data we have. Uh, all, and that is kind of the read-through that was the second part of your question. Uh, when you're looking to safety, we are very comfortable. Go.

Milligrams. We really see this Association being a lot more related to the time in type of management uh by the investigators than than the drug itself. Uh and we do see as I mentioned 1 of the previous uh questions uh on the higher end of the exposure response, we see even further, uh, after see response or deepening. Uh, so when you combine that with for, uh, with another month of of treatments, uh, we should expect, uh, significantly better.

Uh, results here. Not once again. Not that it's needed, right? This is already the best results and on a black study.

Dan Ferry: Thank you. Our next question comes from Ami Fadia. I'm sorry, Ami left the queue. One moment, please. Our next question comes from David Hong with Deutsche Bank. Your line is open.

Thank you. Our next question comes from Amy Faria.

I'm sorry, Amy left. The Q1 moment, please.

Our next question comes from David Hung with Deutsche Bank; your line is open.

Joon Lee: Hi there. Congrats on the data, and thanks for taking my questions. I just wanted to ask about some of these other work that you mentioned you're doing with the program here in terms of, I guess, mood endpoint and in Power 3, looking at a role for monotherapy. How do you envision some of these other endpoints and additional studies here? Are you looking, I guess, to enhance the label or get some label differentiation versus what's currently available and what else is in the pipeline? Thanks.

Marcio De'Souza: Thanks. Thanks, Dave. On the mood benefits that I mentioned a couple of minutes back, that is an expectation that a drug that reduces seizures makes these patients feel more relief from that hypersedipility overactivity and with this mechanism that is known in a specific way to improve mood in general to be positive. So we are looking for adding that as an endpoint, potentially a label claim, of course, based on the results there. On the Power 3 switch to monotherapy study, I think that is a game changer. We haven't really had a drug for many, many years that is able to move to those 100% of the patients there at the beginning versus the 30% on the bottom.

And Empower 3 looking at, uh, you know, a role for Mona therapy, how do you envision some of these, uh, other endpoints and and you know, additional studies here could, uh, are you looking at I guess to enhance the label or get some label differentiation uh, versus what's currently available? And uh you know what else is in the pipeline, thanks.

Thanks. Thanks Dave. So the on the moods uh benefits, right? Uh mentioned a couple of minutes back that is an expectation. That a drug that reduce the seizures, make these patients feel like more relief from that hyper excitability. It's over activity and with this mechanism that is known for in in a specific way to improve most in general to be a positive. So we are looking for adding that as an end point potentially, a label claim, of course, base on, on the results there

Marcio De'Souza: So when you're talking about the refractory, hyper-refractory patients, like fourth, fifth line, as we show on the charts on this slide, we're talking about a $2 to $3 billion market opportunity there. When you move out to the first line, second line, we're talking about several folds that's potential. So from a market opportunity perspective, it makes a lot of sense, number one. From a drug profile, it's the only drug that makes sense. Let me remind everyone that Keppra, which is now the drug that people use off the gate, showed an efficacy of like 30%, basically no seizure-free, and with very similar pharmacological properties and overall toxicological properties of relutrigine. So we're not talking about a high bar to replace that. We're just talking about the fact that no other drugs were able to.

On the Power 3, uh, switch to monotherapy study. I think that is a game changer, right? We haven't really had a drug, uh, for many, many years that is able to move to those 100% of the patients there at the beginning versus the 30% on the bottom. So, when you're talking about the refractory and hyper-refractory patients, like 4th and 5th line, as we show on the charts on the slide, we're talking about a $2 billion to $3 billion market opportunity there. When you move up,

Marcio De'Souza: So that is expected to get off the ground pretty soon and to, if completed before the NDA submission, be on the NDA, potential NDA. If not, to be a quick add-on to the label there.

To the first line Second Line. We're talking about several folds, that's potential. So for the market opportunity perspective, it makes a lot of sense. Uh, number 1, but for a drug profile is the only drug that makes sense, right? Let me remind everyone that Capra, which is now the, the drug that people use of the gates shouldn't have to see of like 30% basically no seizure Freedom, uh, and with very similar pharmacological properties and and overall toxicological properties of our Matrix. So we're not talking about a high bar to replace their, we're just talking about the fact that no other drug were able to. Uh, so that is expected to get off the ground pretty soon. And to if if completed before the NDA submission be on the NDA potential NDA, if not to be a quick add-on to uh to the label there.

Dan Ferry: Thank you. Our next question comes from Ami Fadia with Needham & Company. Your line is open.

Thank you. Our next question comes from Amy Faria with Namin Company. Your line is open.

Ritu Baral: Hi, good morning. Thanks for taking my question and congratulations on this really strong and impressive data. I wanted to better understand the discontinuation rates. If the physicians were allowed to discontinue any background therapies, why did they not do that? For the six or so patients where they were discontinued, was there any change, or can you kind of talk about the change in the efficacy as well as the safety adverse events that were noted after the background therapies were removed? Then maybe a related question on Power 3. What additional data do you think you need to generate, perhaps in an open-label portion, to convince physicians to switch out patients from their existing background therapies and then move patients to relutrigine? Thank you.

Hi, good morning. Thanks for taking my question, and congratulations on this really strong breadth of data. Um,

I wanted to sort of better understand the discontinuation rates. Um, if the physicians were allowed to discontinue any background...

Uh, therapies—why did they not do that? And for the six or so patients where they were discontinued, was there any...?

Change or can you kind of talk about the change in the efficacy, as well as the safety, uh, address events that were noted after, um, the background therapies were removed and then maybe a related question on power 3.

Uh, what additional data do you think you need to generate, uh, perhaps in an open label portion?

to, you know, convince physicians to

Marcio De'Souza: Yeah, absolutely. So Ami, on why people haven't done something, it is going to be kind of a speculation a little bit on my end, right? But it is informed the speculation since we had that conversation. I will refer to one conversation, for example, I had with an investigator in the last few days who was a little bit slow to start reducing. I think his point to us was, and to me particularly, well, you know, we are so used about keep adding and just doing nothing and then cycling these patients on that the reaction time for some of them, this is a big key opinion leader, someone is very important on this space, had a number of patients on the trial. Then when you realize what the first few patients, that was not the case.

Switch out patients from their existing background therapies and then, uh, and then move patients through, uh, the vomit regimen. Thank you.

Yeah, absolutely. So, I mean, uh, on why people haven't done something is going to be...

Kind of speculation or a bit on my ends, right? But it informs the speculation since we had that conversation.

I I'll, I'll I'll refer to 1 conversation. For example, I had with an investigator in the last few days, uh, who was a little bit slow to start reducing. And I think his points to us was and to me, particularly what, you know, we're so used about keep adding and just doing nothing and then cycling, these patients on that, the reality.

Marcio De'Souza: Then for the following ones, he was able to and worked really well. So I think it is a timing thing and really people learning a little bit of the drug. At the end of the day, that is why we did the study as well. On the ones that did remove, I think we mentioned that on the slide as well, it is not only resolved the AEs, right? That was efficacy is not impacted like at all. Well, in the long run, efficacy is actually better on those patients, but we should always be careful to talk about individual patient results on things like this. So that is why we give us, it is not that reducing the background made the patients worse, which is the general concern, right? One would have in linking to your question about PRAX-3.

Action time for some of them. This is a big key opinion leader. Someone's very important in the space at the number of patients on the trial, and then when he realized with the first few patients, that was not the case. And that for the following was...

Uh, he was able to and and, and worked really well. So I think it's a timing thing and and really people learning a little bit the drug at the end of the day. That's why did they study as well?

Because he's actually better with those patients, but we should always be careful to talk about individual patient results on things like this. So that's why we give it to you.

It is not that reducing the background made the patients worse.

Marcio De'Souza: I think that would be concerning if that was the case, but it is not the case at all. In a sense, I think what we established is that the background therapy is not doing anything but causing side effects, and relutrigine is getting these patients better. So a monotherapy study or a switch to monotherapy makes a lot of sense. We pulled a number of physicians on the last few days as they are under CTA with us, and I think that is an incredible enthusiasm for PRAX-3 because they really believe in relutrigine, but they did not have an opportunity to do something like that before with any other drug. So not hearing a lot of concerns. Of course, there are ways to do it. There are dynamics on this study, but not really an overwhelming concern about it.

Which is the general concern, right? I would have in linking to your question about power. I think that would be concerning if that was the case, but it's not the case at all. In a sense, I think what we established.

Is that the background therapy is not doing anything but causing side effects and Burma Gene is getting these patients better. So, uh, a monotherapy study, I switched to monotherapy. Makes a lot of sense, we pulled a number of uh, Physicians on the last few days as they are under CTA with us. And I think that is an incredible enthusiasm for power 3, uh, because they really believe on life, or matrouh Gene, but they didn't have an opportunity to do something like that before, uh, with any other drugs. So, not not hearing a lot of concerns. Of course, there are ways to do it that are dynamics on the study. Uh, but not really an overwhelming concern about it.

Ritu Baral: That's helpful. Thank you.

Marcio De'Souza: Thank you.

That's helpful. Thank you.

Thank you.

Dan Ferry: Thank you. Our next question comes from Jay Olson with Oppenheimer. Your line is open.

Jay Olson: Oh, hey, congrats on these impressive results, and thanks for providing the update. Since you mentioned the observation that seizures beget seizures, is there a way to show that relutrigine could potentially have a disease-modifying benefit?

Thank you. Our next question comes from Jay Olsen with Oppenheimer. Your line is open.

Oh, hey. Congrats on these impressive results, and thanks for providing the update since you mentioned the um,

Observation that seizures beget seizures. Is there a way to show that for Matt Regene could potentially have a disease-modifying benefit?

Marcio De'Souza: Yeah. Thanks, Jay. I would again argue, and I will ask Steve to comment here as well, that that is what we already seen when we have the direct benefit of seizure control and then the indirect benefit of patients just feeling generally better, better moods, better relationship with the site and with their own families, and so on. Ultimately, I think what we are looking for here is to change epilepsy as we know it, right? Take a look at our slides when we are looking to people keep saying 30% of patients are refractory. That is one of the biggest BS that anyone can say in epilepsy. It is like over 60% of those patients are on several therapies, right? That is just not acceptable. Those things are not benign, as we know. So they affect the well-being of patients as well.

Yeah, thanks Jay, the I would again argue. And I'll I'll ask, is T to comment here as well. That that's why we already seen when, uh, we have the direct benefit of seizure control and then the interact benefit of patients just feeling generally better, better moods, better relationship with the sides and with their own families, uh, and so on and ultimately, I think what we are looking for here is to change the plats as we know it. All right, uh, take a look at our our slides. When we're looking to people keep saying 30% of patients are refractory, that's the 1 of the biggest BS that anyone can say in epilepsy, it's like over 60% of those patients are on several therapies, right? The and that is just not acceptable. Like uh those things are not benign as we know, so they are

Marcio De'Souza: When you remove that, get an effective drug that not only reduces the seizures but improves their overall well-being and particularly moods, as we discussed, I think we have an opportunity to really change everything here. Maybe Steve, you can talk about it.

Steve Petro: No, I think it's back to that early point about seizures, beginning seizures, is the disease. That it's a new set point for the brain where a higher level of activity, a higher threshold for triggering seizures, it becomes the new normal. This reduction over time in seizures that we saw and that we've talked about earlier is a sign that we're reversing that process. That can be exactly what you're talking about, disease modification. All the attendant things that happen, if you've got a brain that's hyperexcitable, mood disturbances, and other things emerge, and the fact that we saw changes in other domains, I think it's very encouraging that we are really tackling some fundamental issues of what epilepsy is. We see this across rare, severe epilepsies. We see that common epilepsy is like focal as well.

Fact, that well-being of patients as well. When you remove that get an effective drug that not only reduce the seizures, but improve their overall well-being and particularly moods as we discussed. I think we have an opportunity to really change everything here, but maybe see if we can talk about it. No. And I think it's back to that earlier point about seizures. Beginning seizures is the disease um, that it's a new set point for the brain. We're a higher level of activity, a higher threshold for triggering seizures. It becomes the new normal. And this this um, this reduction over time in seizures that that we that we saw. And that we've talked about earlier is a sign that we're reversing that process so that in in in that can be, you know, exactly what you're talking about disease modification. So and then all the attendant things that happen. If you've got a brain, the type of excitable, um, mood disturbances and other things emerge. And the fact that we saw changes in other domains, I think is very encouraging.

Steve Petro: That it is a disorder of seizures and excitability, and resetting that set point is key to disease modification and improvement across multiple areas.

That we are really tackling. Um, so fundamental issues of of, of of, of the of of of what epilepsy is, we see this across rare, um, severe epilepsy, which seems that common epilepsy? Like focal as well, that it is a is a disorder of seizures and excitability and resetting that that that set point is, is key um, to disease modification and Improvement across multiple areas.

Jay Olson: Thank you for that. Maybe if I could just ask one follow-on. Do these impressive Radiant results give you any hint that relutrigine potentially could have benefit in DE?

Thank you for that. And maybe if I could just ask one follow-on, do these impressive radiant results give you any hint that matching potentially could have a benefit in DE?

Marcio De'Souza: In theory, yes, right? I think we can. The good news is the relutrigine is quite strongly set for DEs, and EMERALD is off the ground that you might have seen on our corporate release a couple of minutes ago. Enrolling patients, we do expect to have very strong enrollment and results there as well on the DE side. There are things, features that are important for DE patients that you might not be able to fulfill with like a solid form that is like vormatrigine. But in theory, right, these drugs are dampening hyper-excitability on a hyper-excitable neuron that is seizing a lot. So yeah, there is no reason to believe not. But we are really looking straight on and quite focused for relutrigine for DEs and for vormatrigine for adult epilepsy.

It it it it, in in theory. Uh, yes. Right. I think we can, with the good news is the religion is quite strongly set for these, and Emerald is off the ground that you might have seen on our corporate release a couple of minutes ago. Uh, enrolling patients. Uh, we do expect to have very strong enrollment and results there as well. Uh, on the G side, uh, that are.

Features that are important for the patients that we might not be able to fulfill with like a solid form. That is, uh, for...

On a hyper-excited side of all neurons, that is seizing a lot. So yes, that is no reason to believe not, but we're really looking straight on and quite focused for Liturgy for these, and for the Matrix in adult epilepsy.

Jay Olson: Great. Thanks for taking the questions.

Marcio De'Souza: Of course. Thank you.

Great. Thanks for taking the questions.

Of course, thank you.

Dan Ferry: Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.

Joon Lee: Hey, good morning, everyone. Thank you for taking the question. Let me extend my congratulations as well on the nice data. I like the chart on slide 13. You have breaking out the efficacy by background meds. I am just wondering, in that vein, if you are kind of pushing on some of the color on the safety profile, do you have a similar slide deck to kind of look at how safety breaks down by background ASMs? Obviously, some of these are pretty potent sedatives. I wonder if there is just a driving force behind some of the divs and dis and somnolence that can be discombobulated from drug. Just to confirm, are these all focal onset patients in this data set, or are there any grand mal patients here? Thanks.

Thank you. Our next question comes from Brian Scy. Your line is open.

Marcio De'Souza: Yeah. So Brian, this is all focal onset seizures. We are going to have the primary channelized later in the year at AS here. So maybe get that out of the way. As you can see on both the demographics table and on that slide, this number sums to much more than 100% in terms of the overall. Patients were in a multitude of anti-seizure medications, which makes that analysis of what is actually the culprit a lot harder. But I think what we can say is we look into not only the ASM they are in, but the actual ASM levels in their blood. When you look into that, it is very clear that a significant proportion of those patients are on toxic concentrations, meaning higher than the maximum allowed concentration in the United States. You do see somewhat of an association on those cases.

Hey, good morning everyone. Thank you for taking the question. And let me extend my congratulations as well on the on the nice data. Um, I like the chart on slide 13. You have breaking out the efficacy by background Med. So I'm just wondering in that vein. If, if on you kind of pushing on on, on some of the color on the safety profile, do you have a similar slide deck to kind of? Look at how safety breaks down by background asm's? Obviously some of these are are pretty potent sedative. So I wonder if there's just a driving force um behind some of the difference. This and and so I'm going to be discombobulated from uh, um, drug and just to confirm are these all focal onset patients in this data set, or are there any Grand now, patients here? Thanks.

Yeah, so Brian, this is all, uh, focused on seizures. We're going to have the uh, the primary generalized later in the year at uh, here. So, maybe get that out of the way. Uh, as you can see on both the demographics table and on that slide. Alright, this number sums to much more than 100% in terms of the overall. So, patients were on a multitude of uh, antiepileptic medications, which makes that analysis of what is actually the culprit a lot harder. But I think what we can say is, as we look into not only the ASM there but the active ASM levels in their blood, right? And what we look into is that it is very clear that a significant proportion of those patients are on toxic concentrations, meaning higher than the maximum allowed concentration in the United States, and you do see.

Marcio De'Souza: So people are now monitoring from a drug monitoring perspective too frequently and heavily these patients. I would argue they should. Obviously, they are a lot more prone to have side effects. One of the reasons why we are being a lot more proactive on the reduction of the dose of the background.

Uh, somewhat of an association, uh, on those cases.

So people are not monitoring in front of the Republic drug monitoring perspective too frequently and happily these patients. I would argue they should, and obviously they are a lot more prone to have side effects. One of the reasons why we're being a lot more proactive on the reduction of the dose of the background.

Joon Lee: Great. Thank you.

Marcio De'Souza: Of course.

Great. Thank you.

Of course.

Dan Ferry: Thank you. Our next question comes from Joon Lee with Truist Securities. Your line is open.

Thank you. Our next question comes from Rudy Lie with Chardan. Your line is open.

Douglas Tsao: Hey, thanks for taking my question. Congrats again on the strong results. Just a quick follow-up to the question regarding the background therapy. Can you provide additional color on the potential impact touching off current background therapies? I am just curious, how would that change your enrollment criteria selecting the right patients for the pivotal trials? What kind of additional data you think would be necessary to support its use in combination with other sodium channel blockers in practice? Thanks.

Hey, thanks for taking my question. Uh, congrats again on the strong results. Uh, just a quick follow-up to the question regarding the background therapy. Can you provide additional color on the potential impact, testing of current?

Background therapies. I'm just curious how that changes your enrollment criteria.

Uh, selecting the right patient for the pivotal trials, and what kind of additional data you think will be necessary to support it, using combination with other sodium channel blockers in practice. Thanks.

Marcio De'Souza: Yeah. I think what you've seen here is the only real sample of how patients are treated currently, right? Unfortunately, I would say, adjunctive therapy on this layering of ASMs is just a common practice. There is no reason to be worried, concerned, about the combination. If anything, right, again, I urge everyone to look into slide 23. This is the lowest rate of side effects on the therapies in development or developed for focal onset seizures, despite the fact that the combination was probably the most aggressive at baseline. So no concern whatsoever. We need to deal with the markets as the markets stand. That's what we are doing here, right? Particularly with over 30% of patients on Xenomate, and I would say that's what the market is. We're very confident that both the safety and the efficacy are incredibly strong there.

Yeah, really. I I think what you've seen here is the only real sample of how patients are treated currently. But uh unfortunately I'll say uh, June 5th therapy on this layering of VA sends is just a common practice, uh, that is no reason to be worried concerns uh, about the combination, if anything. Right? Again, I urge everyone to look into July 23rd. This is the lowest rate of side effects on the, the therapist in developments or developed for, uh, for 4 months at seizures. Despite the fact that the combination was probably the most aggressive,

Marcio De'Souza: So no real expected change other than the instruction, as we mentioned before, for physicians to be more cautious about the reduction on the background ASM.

Joon Lee: Got it. Very helpful. Thanks.

Got it. Very helpful, thanks.

Thank you.

Dan Ferry: Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open.

Thank you. Our next question comes from Rell with TD Cowen. Your line is open.

Ritu Baral: Hi, guys. Thanks for taking the follow-up. I just wanted to ask a little more detail on the side effect profile, and specifically the comment on the severe patients and this comment about recovered and resolved. Can you give us a little more detail on the moderate to severe, and serious side effects and that recovered and resolved comment? Then I have got a follow-up.

Marcio De'Souza: Yeah, yeah. On the severe specifically, we saw that one of the patients had dizziness. I would say that that was clearly on target, and on target is not only for therapy, but for the combinations that they were in. The other ones were background illness, particularly an infection that leads to aspiration pneumonia. I am not too concerned about that. The fact that they all resolved, I think that is the most important, and resolved very quickly is the most important part here. I am not too concerned. I think we wanted to be very transparent and show the rates there and show the results, but not anything we are very concerned about.

Hi, guys. Thanks for taking the follow-up. Um, I just wanted to ask a little more detail on the side effect profile, um, and specifically the comment on the severe patients. Um, and this comment about, um, recovered and resolved—can you give us a little more detail on, um, the moderate to severe, um, and serious side effects and that recovered and resolved comment? And then I've got a follow-up.

Yeah. Yeah, so on this, if you're specifically, um,

To one of the patients, they experienced dizziness. So I would say that.

Uh, that is, was clearly, like on targets, and on target is not only for therapy. But for, uh, the combinations that they were in, uh, the other ones were background illness, like a particular infection, uh, that needs to aspiration pneumonia. So, not too concerned about that. Uh, the fact that they all.

Like resolved, I think it says the most important and resolved very quickly is the most important part here. So, not to concern, I think we wanted to be very transparent and show the rates there and show the results, but not anything where, uh, very concerned about.

Ritu Baral: Was it resolved with removal of drug or adjustment of background meds?

Marcio De'Souza: Oh, very good question. Sorry for misunderstanding before. No, it was actually just resolved with the continuous dosing.

Edict, was it, um, was it resolved with removal of drug or adjustment of background meds?

Oh, very, a very good question. Sorry for misunderstanding before. No, it was actually just resolved, like with the, uh, with conscientious dosing.

Ritu Baral: Okay, that was the follow-up question. Thank you.

Okay. Um,

You.

Dan Ferry: Thank you. I am showing no further questions at this time. I would like to turn the call back over to Marcio for closing remarks.

Thank you. I'm showing no further questions at this time. I'd like to turn the call back over to Marcio for closing remarks.

Marcio De'Souza: Thanks, everyone, for joining. We are thrilled on these results. I think it is important for all of us, but it is particularly important for patients living with focal onset seizures and with epilepsy in general. It is not every day that we get a field that has been going on for like 100 years, a little bit over 100 years since the first treatment, and you can deliver after more than 25 drugs in the market, like over 50% reduction and 60% overall response rate of patients. It is quite remarkable to put in context. I wanted to take a second to show my appreciation for all the patients participating on this study and all the other studies and for everyone at Praxis Precision Medicines and our investigators and site staff. Thank you so much. Exciting days ahead of us.

Oh, thanks everyone for joining. Uh, we are at 3, oh, on this results. I think it's important for all of us, but it's particularly important for patients sleeping with, uh, Pokémon that have seizures and with epilepsy, in general. Uh, it's not every day that we get a field that's been going on for like, a hundred years since the, a little bit over 100 years since the first treatments and you can deliver after more than 25, uh, drugs, uh, in the market like over like 50%, uh, production 60% overall our response rate, uh, patience. It's quite remarkable.

Marcio De'Souza: I appreciate the support and looking forward to interacting with all of you.

To put in contacts. Uh, wanted to take a second to to show my appreciation for all the patients participating on this study and all the other studies. And for everyone at at practice in our investigators and site staff, thank you so much. Exciting days ahead of us, appreciate the support and looking forward to interacting with all of you.

Dan Ferry: Thank you for your participation. You may now disconnect. Everyone, have a great day.

Thank you for your participation. You may now disconnect. Everyone have a great day.