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Operator: Good day, and welcome to the Praxis Precision Medicine's RADIANT Top Line Results and Second Quarter 2025 Financial Results Conference Call. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Dan Ferry of LifeSci Advisors. Please go ahead.
Daniel Ferry: Good morning, and welcome to the Praxis Precision Medicine's RADIANT Top Line Results and Second Quarter 2025 Financial Results Conference. This call is being webcast live and can be accessed on the Investors section of the Praxis website at www.praxismedicines.com. Please note that remarks made during this 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 time lines and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking 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. Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis; Tim Kelly, Chief Financial Officer; and Steve Petrou, 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?
Marcio Silva De'Souza: Good morning, everyone, and welcome to the RADIANT's Top Line Results presentation. We're incredibly excited to share this best- in-disease results with all of you. Before we begin, I would like to note that today's presentations contain forward-looking statements. For complete disclosures, please refer to our latest SEC filings. Praxis is in an incredible position to bring innovative drugs to patients with CNS disorders. We have 4 late-stage assets, one of which we are discussing here today, and we expect 5 clinical readouts within the next year. There is no small feat. This progress is powered by our 2 robust platforms, enabling current developments and future CNS drug innovation. Our cash runway extends into 2028, supporting our ambitious clinical agenda. Today, we'll discuss the RADIANT results for vormatrigine. But it's worth taking a few moments to remind everyone of the rich and deep pipeline we have with multiple readouts coming out in the next several quarters, which will enable Praxis 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 now 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 a constant ASM cycling, and we believe vormatrigine can deliver on that. Starting with today's results, vormatrigine is showing best-in-disease efficacy in the RADIANT study. That should be enough to be excited. We should not minimize the further differentiation of vormatrigine with current and in development therapies being the only drug to combine, once daily administration, fast action, no-food effect ideal tolerability and no meaningful drug-drug interactions, 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 results, 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 demand for focal, even after we announced the closing of the enrollment to the sites, demonstrate the effectiveness of our recruitment capabilities. The same engine is already at play for the POWER1 and soon to be for the POWER2 and POWER3 studies. We have so far completed screening of 99 patients in those 61 as of July 25. We expected to complete the study in the near future with approximately 75 patients dosed. Today, we will review data from 37 focal patients who completed the study for efficacy so far. We also review the safety for the overall cohort of the 61 patients who have been dosed. We 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?
Steven Petrou: 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 vormatrigine 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 antiseizure medications. Looking ahead, we expect the population in our upcoming POWER1 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. Now, let's turn to the part that we're most excited about, the results. Vormatrigine 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 1 of the highest responder rates we've seen in recent epilepsy trials, and it speaks to the potential impact vormatrigine 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 1, 54% of patients had already responded. That number climbed to 67% by week 8, showing a clear and encouraging trend of improvement. 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 vormatrigine's potential but also sets the stage for what we hope to see in the longer 12- week POWER1 and POWER2 studies. Looking more closely at the data, for vormatrigine'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 loads 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's 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. following widespread adoption of cenobamate. In fact, 30% of RADIANT participants were already on cenobamate meaning vormatrigine 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 remain consistently strong. Patients showed excellent responses, whether they were on 1 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 vormatrigine'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. Vormatrigine demonstrated a favorable overall profile. Most adverse events were mild to moderate and tended 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. Importantly, in 6 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 vormatrigine itself but rather a manageable interaction dynamic that can be addressed with appropriate background therapy management. 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 vormatrigine's potential to make a real difference for people living with refractory epilepsy. With that, I'll now hand the call back to Marcio.
Marcio Silva 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 POWER2. 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 POWER2 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 inflationary we learned in the RADIANT study is the reported positive impact in moods observed in patients. With that in mind, we decided to include a depression and mood endpoints to the POWER2 design. We're ready to start rolling out POWER2, and it goes without saying that the full force of the Praxis recruitment engine would be at it. The final design of POWER2 enroll approximately 400 refractory epilepsy patients, testing vormatrigine dose 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. analysis in patients with focal epilepsy conducted by Praxis, which covers almost 0.5 million patients worth of data. The message is very clear. The majority of the patients are not doing okay, and virtually 2/3 of them fail their first-line treatment. And after that, a very improvised layering of multiple agents begin. This is not good for patients or the health care system. Clearly, there's a critical need for simpler, more effective treatments vormatrigine, ones that combine the fast-acting mechanism with minimum restrictions and high effectiveness. With that in mind, we'll be launching POWER3, which aims to establish vormatrigine as stand-alone therapy, enrolling refractory epilepsy patients transitioning off currently ASM. This 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 POWER3 in early 2026. To wrap up the call about vormatrigine, it's incredibly exciting to be 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 group. The RADIANT results significantly bolster our confidence in the ongoing and upcoming studies for vormatrigine. Before we move to Q&A, and reminding that today's results is about celebrating vormatrigine, I want to emphasize that Praxis remains deeply committed to revolutionize epilepsy treatments from common focal epilepsy to rare DEE conditions. I'm sure we 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. Lastly, we extend our sincere thanks to our investigators, patients, site staff and Praxis team for their contribution to the success of the epilepsy program in overall. We now open the call to Q&A. Operator?
Operator: [Operator Instructions] Our first question comes from Yasmeen Rahimi with Piper Sandler.
Yasmeen Rahimi: Team, congrats really to the outstanding data, both in treatment response as well as seizure free, especially at the majority of the patients are on background therapy. I guess the first question is, if you look 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 one. And then a question for number 2 is just given the incredible execution into RADIANT and that and you provide a color around POWER2 reading out in -- POWER2 finishing in the back half of 2026, could you maybe help us understand sort of, I think we get the question a lot, what were sort of the nuggets that leads you to execute really strongly through the study? And then the timing of POWER1, I think a lot of -- it sounded like you're on track to finish POWER1 at year-end, but if you could just reconfirm guidance around timing of POWER1, that could be very helpful.
Marcio Silva De'Souza: Thanks, Yas, like 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 on the specifics for the background, if you look across Keppra or any of the SV2As and it's on our Slide 13, right, we saw incredibly robust effects on sudden channel blockers in general, some patients were on 1, some patients were on 2 like you wouldn't expect much of an effect there. I think that was some of the skepticism before, and we're seeing incredibly robust effect 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 cenobamate. This was not your mildly treated like a run-of-the-mill epilepsy patient. Then on those patients, we're seeing over 55% of 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 is really moving towards first therapy and first line. And that's why we're starting the POWER3 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 check mark on our ability to recruit this population that as you've seen on the demographics slide, is your classical refractory seizing a lot multi-treated patient population in the United States and in Europe. 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 Power1. The acceleration we did in our corporate release in our Form 10-Q, which should be filed right now, and you can refer to like reinforce the guidance that we previously gave on finalizing POWER1 this year. POWER2 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 are 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, 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. So that is going incredibly well. So we're going to transfer that enthusiasm towards POWER2, and pretty soon in the future POWER3 as well. So it's on and all. It's 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 POWER1 and to getting POWER3 and getting that registrational. It's 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 of our execution and our team's focus on getting these patients on these studies.
Operator: Our next question comes from Ritu Baral with TD Cowen.
Ritu Subhalaksmi Baral: Congratulations on this on this really, really good data. I've gotten a bunch of questions this morning. Just being driven by this 22% seizure-free rate and the sort of large percentage of patients that responded very rapidly. Marcio and Steve, what do you think is driving this increase in efficacy on all these measures? Even after steady-state plasma is achieved in patients and is your -- do you have any exposure response analysis done, which is contributing to the 20-milligram dose that you now plan on including in POWER2? And then I've got just a quick housekeeping follow-up.
Marcio Silva De'Souza: So we do have the exposures, and I would say that the raw exposures are already quite well processed and the preliminary exposure response well underway as well. So I'll make a couple of comments about that, and then I'll hand over to Steve to talk about why we are -- we were expecting and we are seeing these phenomenal results. So we do see steady state being reached quite quickly here between the first and the second week of treatment. As you've seen on these slides, off the gate to get very good results, it deepens 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? Like the patients don't see otherwise, we'll observe them for a week and then just treat for a week or 2 afterwards. And it's the overall month. I think the metric here. But we do see less -- I think the overall concept is that less seizures leads to less seizures. So we see this deepening over time, which bodes incredibly well for POWER1, which is 12 weeks long. And POWER2 is going to be 12 weeks long as well on that regard. The 20-milligram dose that we are already using for the first 6 weeks of POWER1 is reviving to the range where you are seeing this incredible efficacy, clearly in the 30 as well, but what you've seen is a potential for a fairly significantly higher when you go to the much higher side of the exposure of these patients to get an even bigger results here. Now that we need it, not like this is the highest seizure reduction ever seen on an epilepsy study, not that we need anymore, but I think these patients do deserve more and they're going to drive that. And that's why we added the 40-milligram. So in a sense, it's good to be stepping into POWER2, expecting all 3 dose to be quite effective and giving this flexibility for the patients. But maybe Steve can talk about why we think the dippening is granted.
Steven Petrou: Just speaks to the issue you raised, Marcio, about fewer seizures causing fewer seizures. And 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 or 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. So we just think it's really the opposite corollary of increasing seizures as the patient first presents. And there's well-known physiological mechanisms, homeostatic plasticity, et cetera, that are known to underlie this phenomenon.
Ritu Subhalaksmi Baral: Super helpful. And then, Marcio, you knew this was coming. The upcoming POWER1 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? And will you announce completion of enrollment for that study?
Marcio Silva De'Souza: Yes, we probably will announce the completion. And I would say, at this point today is the day to celebrate RADIANT. But yes, I could see this coming. I appreciate you surpassing with that. The enrollment is incredibly strong. I just had a call this morning with most investigators and enthusiasm of everyone that is on POWER1 is really great to see. I know it was in the slides, and I reinforce it, but the RADIANT -- 1 of the things on RADIANT that we are not expecting was really this overwhelming feedback from patients 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 that is certainly helping with even more patients being funneled towards this study versus other things going on out there.
Operator: Our next question comes from Joon Lee with Truist Securities.
Joon So Lee: Congrats on the data. Can you elaborate a little bit more on this discontinuation rates in the RADIANT and how that was imputed into the seizure reduction data, if at all? And also for the forthcoming POWER1, would it be fair to assume that placebo rates will be lower than those reported for cenobamate and drug given the more refractory population in POWER1?
Marcio Silva De'Souza: So why we are -- we think we can do better on the discontinuation, right? Like if you look into competitively our other studies, it's fairly similar. As I'm sure you've already done the comparison in overall. So not, but completely satisfied are there yet because we've seen what happens when investigators like actually follow the bills they had on the protocol, it doesn't happen, right? Or it happens at a variable rate. And I think that's why we're going to see moving forward. Having talked with some of them already over the weekend and so on, I think some regrets they would then have removed some of the drug. So not as much on the impact to your question on the ability to reduce seizure, but just that is a lot on top of these patients, and I think that that's what is leading primarily here for patients don't want to stay. It was also an easy study to come out as well, right? When you are in the open-label setting, it's certainly more reports of side effects in general and easier to discontinue. So I'm not completely surprised a little bit higher than we expected, but it's still lower than cenobamate competitive to other drugs in the market with lower efficacy. And you mentioned what we should be expecting for POWER1. I agreed in general, what you're seeing in this patient population are 2 things, right? So 1 is the background, as you mentioned, very difficult, very refractory in general and then the second is really the quality of the sites, the quality of the patients are coming in. The stability of these patients on their seizures beforehand. So I think when you get like 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.
Operator: Our next question comes from Douglas Tsao with H.C. Wainwright.
Douglas Dylan Tsao: Congrats on the data. I guess as a starting point, in terms of the added effect of the increasing efficacy that we see over time, that was something that we saw with vormatrigine as well. And I'm just curious, the 2 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 detindling effect, which sort of I think Steve sort of talked to I think in response to Ritu's question, and then I have a follow up.
Steven Petrou: Yes, maybe just to further what I said before, Doug, yes, that's very specific and different to how any other molecule interacts with the sodium channel, their biophysical profile. And 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 it's growing because we're having such good -- acute efficacy that encourages this longer-term efficacy to grow over time. So very much associated with our physical character.
Douglas Dylan Tsao: Okay. Great. And I guess on the side effect profile, I'm just curious Marcio or Steve, to the extent that you've been able to sort of detangle the effect that some of these side effects were or AEs were related to vormatrigine versus the background therapy and as you look to the power studies, sort of thinking about enabling some sort of reduction dosing in background ASMs, which obviously probably contribute to many of the side effects experienced by patients.
Marcio Silva De'Souza: Yes. So absolutely right. But maybe before they all ground us on the table on our Slide 23. The vormatrigine treatment emerging AEs is over 20% lower than any other drug out there, 20% less patients. But if you're talking about any other therapeutic area, this is like 100 miles from anything else. On CNS-related, it's about 20% as well. So we're already at other like universe when it comes to these other drugs that are unfortunately in the background, right? . So we can't disentangle what these other things are doing, but what we know because we ran the experiment is, it gets reduced or removed when the background drugs are reduced, which ultimately is what these patients do, right, in what the physicians there. So we see that it's incredibly positive, not only for patients continuing RADIANT since we have significant more now and for open- label extension as well. But for the POWER1 and POWER2 and potentially POWER3 studies as well. So 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's why we're moving forward.
Douglas Dylan Tsao: Okay. And if I can, 1 follow-up. I'm just curious on the mood benefits that you saw. I'm just curious, is that based on sort of anecdotal feedback? Or was there any kind of sort of inventory on emotional taken?
Marcio Silva De'Souza: Yes. So you will start systematically reported by sites. But unfortunately, we have not designed an instrument to collect that from the very beginning. And that's where we are incorporating the power to design. It's not completely unexpected, right? I think there's other drugs in this class that have approval for like bipolar, for example, like lamotrigine, but they just can't be used probably because of the other issues, including like the allergic reactions to the drug. So not -- again, not completely unexpected, but you are the very welcome comments that we got across the board from investigators.
Operator: Our next question comes from Yatin Suneja with Guggenheim.
Yatin Suneja: Guggenheim Securities, LLC, Research Division Let me add my congratulations. Very nice results, again, congratulations to the team. So a couple for me. So the first 1 is, could you talk about the kinetics of responses 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'd probably get more benefit. And 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. So that's first. 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? And then finally, on the safety, which I'll ask, I mean you should be very comfortable with the safety, especially the call it ability if you are going with the 40-milligram in the future studies. So, yes, those are the 3 questions.
Marcio Silva De'Souza: On the kinetics of the response, it is very clear, if we thought it would be this ingenuous to just get a straight line there to fit like a linear, but if that was the case, and you can do yourself since the data, you would see a very significant dippening between the first month and the second month, which we expect to continue as we treat this patient further. So for POWER1, the translation should be even deeper response there. Of course, going to have to wait for that study to read out, but that is the expectation based on the data we have. And that is kind of the read-through that was the second part of your question. When you look into safety as we're 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. And we do see, as I mentioned, one of the previous questions, on the higher end of the exposure response we see even further efficacy response or dippening. So when you combine that, we form with another month of treatment, we should expect significantly better results here, not once again, not that it's needed, right? This is already the best results in an epilepsy study.
Operator: Our next question comes from Ami Fadia. I'm sorry, Ami left the queue. Our next question comes from David Hoang with Deutsche Bank.
David Timothy Hoang: Congrats on the data. So 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 POWER3 looking at a role for monotherapy. How do you envision some of these other endpoints and additional studies here could -- 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?
Marcio Silva De'Souza: So on the moods benefits, right, as I mentioned a couple of minutes back, that is an expectation that a drug that reduces the seizures make these patients feel like more relief from the hyperexcitable overactivity and with this mechanism that is known for -- 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 POWER3, switch to monotherapy study, I think that's a game changer, right? 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. So when you're talking about the refractory -- hyperrefractory patients like fourth or fifth line, as we show on the chart on this slide, we're talking about a $2 billion to $3 billion market opportunity there. When you move up to the first line, second line, we're talking about several folds that potential. So from a market opportunity perspective, it makes a lot of sense, number one. But from a drug profile is the only drug that makes sense. Well, 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 freedom and with very similar pharmacological properties and overall toxicological properties of vormatrigine. So we're not talking about a high bar to replace there. We're just talking about the fact that no other drug we're able to. So that is expected to get off the ground pretty soon and to, if completed before the NDA submission beyond the NDA, potential NDA, if not to be a quick add-on to the label there.
Operator: Our next question comes from Ami Fadia with Needham & Company.
Ami Fadia: Congratulations on this really strong and impressive data. I wanted to sort of better understand the discontinuation rates. If the physicians were allowed to discontinue any background therapies, why did they not do that? And for the 6-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 are removed. And then maybe a related question on POWER3, 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 through vormatrigine?
Marcio Silva De'Souza: Yes, absolutely. So Ami, on why people haven't done something, it's going to be kind of speculation on a bit on my end, right? But it informed the speculation since we had that conversation. And I'll 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. And I think his point to us was, and to me, particularly. Well, we're 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 for the space and the number of patients in the trial. And then when you realize was the first few patients that was not the case and that for the following ones, was able to and worked really well. So I think it's a timing thing and really people learning other with the drug at the end of the day, that's why we did the study as well. On the ones that did remove, I think we mentioned that on the slide as well, it's not only resolved the AEs, right? That was -- efficacy is not impacted like at all. 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's why we give us -- it is not that reducing the background made the patients worse, which is the general concern, right? So one would have and linking to your question about POWER3, 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 vormatrigine is getting these patients better. So a monotherapy study or switch to monotherapy makes a lot of sense. We pulled a number of physicians on the last few days as they are under CDA with us, and I think that is an incredible enthusiasm for POWER3 because they really believe on like vormatrigine, but they didn't 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 concerned about it.
Operator: Our next question comes from Jay Olson with Oppenheimer.
Jay Olson: 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 for vormatrigine could potentially have a disease-modifying benefit?
Marcio Silva De'Souza: Yes. I would, I'll, again, argue and I'll ask Steve to comment here as well that that's what we're already seeing 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. And ultimately, I think what we are looking for here is to change the plans as we know it. Take a look at our slides when we're looking to, people keep saying 30% of patients are refractory that's 1 of the biggest PS that anyone can say in epilepsy. It's like over 60% of those patients are on several therapies, right? And that is just not acceptable, like those things are not benign as we know, so they affect the well-being of patients as well. When you remove that, get an effective drug that not only reduce procedures, 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, Steve, you can talk about it.
Steven Petrou: And I think it's back to that earlier point about seizures begetting seizures is the disease, but 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. And this reduction over time in seizures that we saw and that we talked about earlier, is a sign that we're reversing that process. So -- and that can be exactly what you're talking about, disease modification. So -- and then all the attended 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 what epilepsy is. And we see this across rare, severe epilepsies. We see this in common epilepsies like focal as well, but it is a disorder of seizures and excitability and resetting that set point is key to disease modification and improvement across multiple areas.
Jay Olson: And maybe if I could just ask 1 follow-on. Do these impressive RADIANT results give you any hint that vormatrigine potentially could have benefit in DEE?
Marcio Silva De'Souza: In theory, yes, right? I think we can with -- the good news is the relutrigine is quite strongly set for DEEs 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 DEE side. That are things, features that are important for DEE patients that we might not be able to fulfill with like a solid form that is like vormatrigine. But in theory, right, these drugs are dampening hyperexcitability on a hyperexcitable neuron that is seizing a lot, so yes, there is no reason to believe not, but we're really looking straight on and quite focused for lamotrigine for DEEs and for vormatrigine for adults epilepsy.
Operator: Our next question comes from Brian Skorney with Baird.
Brian Peter Skorney: 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 med, so I'm just wondering in that vein, if 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 stand by background? ASMs, obviously, some of these are pretty potent sedatives. So I wonder if it's just a driving force behind some of the dips and somnolence that could be discombobulated from drug? And just to confirm, are these all focal onset patients in this data set? Or are there any grand mal patients here?
Marcio Silva De'Souza: Yes. So, Brian, this is all focal onset seizures. We're going to have the primary channelized later in the year at AS here, so maybe get that out the way. As you can see on both the demographics stable and on that slide, right, this number sums to much more than 100% in terms of the overall. So patients were in a multitude of antiseizure medications, which makes that analysis of what is actually the culprit, a lot harder, but I think what you can say is we look into not only the ASM their end with the active ASM levels in their blood, right? And 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. And you do see somewhat out of an association on those cases. So people are not monitoring from therapeutic drug monitoring perspective to frequently and heavily these patients, I would argue they should and obviously, they are a lot more prone to have side effects. And one of the reasons why we're being a lot more proactive on the reduction of the dose of the background.
Operator: Our next question comes from Rudy Li with Chardan.
Guofang Li: Congrats again on the strong results. Just a quick follow-up to the question regarding the background therapy. So can you provide additional color on the potential impact touching of current background therapies. I'm just curious how that change your enrollment criteria connecting the right patients for the pivotal trials? And what kind of additional data you think will be necessary to support its use in combination with other sodium channel blockers in practice?
Marcio Silva De'Souza: Yes. Rudy, I think what you've seen here is the only real sample of how patients are treated currently. Unfortunately, I would say, adjunctive therapy on this layering of ASMs is just a common practice. There is no reason to be where it's concerned about the combination. If anything, again, I urge everyone to look into Slide 23. This is the lowest rate of side effects on the therapeutic developments are 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 market stands and that's what we are doing here. Particularly, with over like 30% of patients on cenobamate, I would say that's what the market is. We are very confident that both the feds and the efficacy are incredibly strong there. So no real expected change other than the instructions, as we mentioned before, for physicians to be more cautious about the reduction on the background ASM.
Operator: Our next question comes from Ritu Baral with TD Cowen.
Ritu Subhalaksmi Baral: 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? And then I've got a follow-up.
Marcio Silva De'Souza: Yes. Yes. So on the severe specifically, Ritu, one of the patients had a dizziness. So I would say that, that was clearly like on targets and on targets not only for therapy, but for the combinations that they were in. The other ones were background illness, like particularly an infection that leads to aspiration pneumonia. So not too concerned about that. The fact that they all like resolved, I think that's the most important and resolved very quickly the most important part here. So not too concerned. I think we wanted to be very transparent and show the rates there, show the results, but not anything we're very concerned about.
Ritu Subhalaksmi Baral: Was it resolved with removal of drug or adjustment of background meds?
Marcio Silva De'Souza: Very good question. Sorry for misunderstanding before. No, it was actually just resolved like with continuous dosing.
Ritu Subhalaksmi Baral: Okay. Okay. That was -- that was the follow-up question.
Operator: I'm showing no further questions at this time. I'd like to turn the call back over to Marcio for closing remarks.
Marcio Silva De'Souza: Thanks, everyone, for joining. We are thrilled on these results. I think it's important for all of us, but it's particularly important for patients living with focal onset seizures and with epilepsy in general. It's not every day that we got a field that's been going on for like 100 years since the -- a little bit over 100 years since the first treatment and you can deliver after more than 25 drugs in the market like over -- like 50% production, 60% overall response rate of patients. It's quite remarkable to put in context, I wanted to take a second to show my appreciation for all the patients participating in this study and all the other studies and for everyone at Praxis and our investigators and site staff. Thank you so much. Exciting days ahead of us. I appreciate the support and looking forward to interacting with all of you.
Operator: Thank you for your participation. You may now disconnect. Everyone, have a great day.