Praxis Precision Medicines, Inc. Q2 FY2025 Earnings Call

Good day, and welcome to the Praxis Precision Medicine's RADIANT Top Line Results and Second Quarter 2025 Financial Results Conference Call. 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.

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 timelines and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, 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?

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. 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, demonstrates the effectiveness of our recruitment capabilities. 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.

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 one 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.

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 PIs 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 on moods observed in patients. With that in mind, we decided to include 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 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 on 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 begins. This is not good for patients or the healthcare system. Clearly, there's a critical need for simpler, more effective treatments, like 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 a stand-alone therapy, enrolling refractory epilepsy patients transitioning off current ASMs. This study leverages historical understanding benchmarks and safety measures to protect the integrity of the patients and the results of it. We plan to initiate POWER3 in early 2026. To wrap up the call about vormatrigine, it's incredibly exciting to be at a point where we can confidently say it has emerged as the 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 vormatrigine. Before we move to Q&A, and reminding that today's results are about celebrating vormatrigine, I want to emphasize that Praxis remains deeply committed to revolutionizing epilepsy treatments from common focal epilepsy to rare developmental and epileptic encephalopathies. 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 the Praxis team for their contribution to the success of the epilepsy program overall. We now open the call to Q&A.

Our first question comes from Yasmeen Rahimi with Piper Sandler.

Team, congratulations on the impressive data regarding treatment response and seizure freedom, particularly since most patients are on background therapy. My first question is whether you were able to determine if there was a difference in response rates among patients taking different products as background therapy. The second question relates to the excellent execution in the RADIANT study. Given the insights you provided about POWER2 concluding in the latter half of 2026, could you share what key factors contributed to your strong performance throughout the study? Additionally, regarding the timing of POWER1, it seems you are on track to complete it by year-end, but could you please confirm your guidance on the timing?

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 sodium channel blockers in general, some patients were on one, some patients were on two like you wouldn't expect much of an effect there. I think that was some of the skepticism before, and we're seeing an 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 where 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 and 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 with our execution and our team's focus on getting these patients on these studies.

Congratulations 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 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.

We have identified the exposures, and I can say that the raw exposures have been processed effectively, with the preliminary exposure response making good progress. I’ll share a few thoughts on this before passing it over to Steve to explain the reasons behind the impressive results we are witnessing. We are observing that a steady state is reached fairly quickly between the first and second weeks of treatment. As shown in the slides, we are getting excellent results right from the start, which improves significantly. We believed that the most scientifically relevant way to present the data was by focusing on the lowest points in the charts because epilepsy isn’t a weekly phenomenon; patients aren’t just observed for a week and then treated for a week or two. It’s about the overall month that matters. The key takeaway here is that fewer seizures lead to fewer seizures. We are seeing this increase in efficacy over time, which is very promising for POWER1, which lasts 12 weeks, and POWER2 will also span 12 weeks. The 20-milligram dose we are using for the initial six weeks of POWER1 is yielding remarkable efficacy, especially at the 30-milligram dose. We’ve also observed potential for significantly greater effects when patients are exposed to higher dosages. While this isn't the highest seizure reduction ever recorded in an epilepsy study and while we may not need more than this, I believe these patients deserve more, and they will be the drivers of that progression. That’s the reason we’ve introduced the 40-milligram dose. Moving into POWER2, we expect all three dosages to be quite effective, providing flexibility for the patients. Perhaps Steve can elaborate on why we believe this deepening of efficacy is warranted.

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.

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 the year. Is there any more granularity that you can give us around where enrollment currently stands? And will you announce the completion of enrollment for that study?

Yes, we will likely announce the completion. Today is a day to celebrate RADIANT, and I anticipated this moment. The enrollment is exceptionally robust. I spoke this morning with most investigators, and their enthusiasm for POWER1 is really encouraging to see. I want to emphasize that one unexpected aspect of RADIANT has been the overwhelmingly positive feedback from patients and investigators regarding their improved moods and better coping abilities. This positive response is certainly helping to attract even more patients to this study compared to other ongoing studies.

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 other drugs given the more refractory population in POWER1?

We believe we can improve on the discontinuation rates. When we compare our studies with competitors, the results are quite similar. However, we are not completely satisfied yet, as we've observed that investigators often do not adhere to the protocols as expected, which can vary. I have spoken to some investigators recently, and they expressed regret about having removed some of the drug. This does not significantly impact the effectiveness in reducing seizures but contributes to patients wanting to leave the study. The open-label nature of the study makes it easier for participants to report side effects and discontinue. While I was somewhat surprised by the higher discontinuation rate, it remains lower than cenobamate when compared to other drugs with lower efficacy on the market. Regarding POWER1, I generally agree with your observations. There are two main issues in this patient population: the demographic's challenging nature and the overall quality of the investigation sites and incoming patients. A higher number of patients per site, better assessment quality, and more stability in terms of seizure control prior to the study will likely lead to lower potential placebo rates.

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 two molecules are similar in many respects. Do you think that is a function 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 about in response to Ritu's question, and then I have a follow up.

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.

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 or adverse events 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.

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 in another like universe when it comes to these other drugs that are unfortunately in the background. 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 significantly 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.

Okay. And if I can, one 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?

Yes, we will begin systematically reporting by sites. However, we did not create a method to collect that information from the onset. We are integrating the ability to design now. This situation is not entirely unexpected; there are other drugs in this class, like lamotrigine, approved for conditions such as bipolar disorder, but they cannot be used effectively due to other complications, including allergic reactions. Again, while this is not fully surprising, we appreciate the positive feedback we received from investigators.

Let me add my congratulations. Very nice results, again, congratulations to the team. So a couple for me. So 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? 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 a 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 three questions.

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 it yourself since the data, you would see a significant dippening between the first month and the second month, which we expect to continue as we treat these patients further. So for POWER1, the translation should be an even deeper response there. Of course, we're 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 in one of the previous questions, that 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.

Congratulations on the data. I wanted to ask about the other work you're doing with the program regarding the mood endpoint and POWER3, specifically in relation to its potential role for monotherapy. How do you see these additional endpoints and studies enhancing the label or providing differentiation from what's currently available and what else is in the pipeline?

So on the mood benefits, right, as I mentioned a couple of minutes back, that is an expectation that a drug that reduces seizures makes these patients feel more relief from the hyperexcitable overactivity and with this mechanism known 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, the 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 hyper-refractory 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, it 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 here. We're just talking about the fact that no other drug was 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.

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 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 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?

Yes, absolutely. Ami, regarding why some people haven't taken action, I can only speculate a bit based on our discussions. For instance, I spoke with an investigator recently who was initially slow to begin reducing treatment. His feedback highlighted that they were accustomed to simply adding therapies and cycling patients without much change, which affected their response time. This investigator is a key opinion leader in this field, and the number of patients in the trial is significant. It became clear that for the initial patients, this approach didn't apply, but for those that followed, he was able to reduce treatment successfully, which yielded good results. I'll attribute this to timing and the learning curve with the drug, which is one reason we conducted the study. Regarding those who did discontinue their background therapy, as we've indicated in our materials, not only have their adverse events resolved, but their efficacy hasn't been compromised. In fact, over time, those patients may show improved efficacy. We must be cautious when discussing individual patient outcomes, which is why we specify that reducing background therapy didn't negatively affect patients, despite common concerns. Linking this to your question about POWER3, it would be worrying if reducing therapy harmed patients, but that's not the case. Our findings suggest that background therapy contributes mainly to side effects, while vormatrigine is effectively improving patient outcomes. Therefore, conducting a monotherapy study or transitioning to monotherapy seems very logical. Recently, we surveyed several physicians engaged in a confidential agreement with us, and there is substantial enthusiasm for POWER3. They genuinely believe in vormatrigine but have not previously had the chance to switch therapies as we propose with any other drug. While there are considerations regarding the dynamics of this study, we haven't encountered significant concerns thus far.

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?

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 relationships 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 landscape 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 one of the biggest points that anyone can say in epilepsy. It's 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 reduces procedures but improves 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.

And I think it's back to that earlier point about seizures begetting seizures as 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 that 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.

And maybe if I could just ask one follow-on. Do these impressive RADIANT results give you any hint that vormatrigine potentially could have benefit in developmental and epileptic encephalopathies?

In theory, yes. We believe we can achieve this. The good news is that relutrigine is well-positioned for developmental and epileptic encephalopathies (DEEs), and Emerald is now operational, as you may have noticed in our recent corporate release, which includes patient enrollment. We anticipate robust enrollment and positive results in that area as well. These aspects are essential for DEE patients, which we might not be able to address with a solid formulation like vormatrigine. However, in theory, these drugs help reduce the hyperexcitability in neurons that are frequently seizing, so we see no reason to doubt their potential. Our primary focus remains on lamotrigine for DEEs and vormatrigine for adult epilepsy.

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 medications, 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 in somnolence that could be discombobulated from the drug? And just to confirm, are these all focal onset patients in this data set? Or are there any grand mal patients here?

Yes. So, Brian, this is all focal onset seizures. We're going to have the primary channelized later in the year to maybe get that out of the way. As you can see on both the demographics slide 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 ASMs they’re in 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 a therapeutic drug monitoring perspective too 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.

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 changed your enrollment criteria connecting the right patients for the pivotal trials? And what kind of additional data do you think will be necessary to support its use in combination with other sodium channel blockers in practice?

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 that 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 fields 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.

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.

Yes. Yes. So on the severe specifically, Ritu, one of the patients had dizziness. So I would say that was clearly like on target 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, show the results, but not anything we're very concerned about. 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.

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