Praxis Precision Medicines, Inc. (PRAX) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines' Corporate Update Conference Call. [Operator Instructions] Please note that today's conference is being recorded. I will now hand the conference over to your speaker host, Daniel Ferry. Please go ahead.

Good morning, and welcome to Praxis Precision Medicines' EMBOLD Study Results Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com. This call is also being recorded. Please be reminded 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, this 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 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. Leading the call today will be Marcio De'Souza, President and Chief Executive Officer of Praxis. Joining Marcio on the call are Dr. Steve Petrou, Co-Founder and Chief Scientific Officer; and Tim Kelly, Chief Financial Officer. After providing the top line results of our EMBOLD study, there will be a brief Q&A session in which Marcio, Steve and Tim will be available to answer your questions. With that, it's my pleasure to turn the call over to Marcio.

Thanks, Dan, and good morning, everyone. I'm very excited to share with you some results from our EMBOLD study in DEEs. They mark a significant advancement in our ongoing commitment to improve treatment outcomes for patients. Firstly, we observed a 46% placebo-adjusted seizure reduction across the study, it's a truly remarkable in such a severely affected population. In terms of safety, a critical aspect of any treatment, but particularly important in all DEEs where patients tend to be heavily medicated, relutrigine was well tolerated and no discontinuation due to AE was observed. This underscored the potential for patients who have struggled with other medications and treatments. Most notably, we achieved an unprecedented level of seizure freedom, with 5 patients remaining seizure-free for longer than 28 days. No patient was seizure-free for such a longer period of time before entering the study or experienced such effect while on placebo. I can't say how excited we are for those patients and for the broader community and the implications it brings to the epilepsy and DEE community in general. Additionally, relutrigine-treated patients demonstrated a 75% median seizure reduction during the long-term portion of the study, indicating not only immediate but also enduring benefits for patients. Moreover, clinicians and caregivers have reported a disease-modifying impact observing substantial improvements in patients' daily functioning. And lastly, these promising results have propelled us to initiate and expand the registration cohorts, aiming to further validate the drug's benefit and support its journey towards regulatory approval. Those results position practice further into disrupting the epilepsy market. SCN2A, and SCN8A alone, with over 5,000 patients in the U.S. and no approved treatment, are expected to have a peak revenue potential of more than $500 million. On top of that, the validation of the safety and efficacy brought by EMBOLD allow us to confidently expand towards the broader DEE market. particularly the well-established population of patients already using suboptimally from both safety and efficacy sodium channel blockers. That opportunity alone is expected to be well over $2 billion. Those are truly exciting moments. But before I continue to discuss the results of EMBOLD, let me hand the call over to Steve Petrou, our Co-Founder and CSO, who will discuss key aspects of DEE and relutrigine. Steve?

Thanks very much, Marcio, and I appreciate everyone joining us this morning. Before we delve into the specifics of the trial, I'd like to provide some background on the 2 disorders we studied and discuss the broader context of developmental and epileptic encephalopathies or DEEs. Additionally, I'll explain why we believe that sodium channel modulation by relutrigine has the potential to significantly improve outcomes, not only for the specific disorders we studied in EMBOLD but for DEEs more broadly. As you may know, DEEs encompass a wide range of severe epilepsies, many of which are driven by mutations in one of around 900 known genes. These conditions vary in severity, but they all profoundly impact patients' lives, often leading to significant developmental delays and frequent debilitating seizures. The burden on caregivers is equally substantial as these diseases often require regular hospital visits and intensive ongoing care. Additionally, the high seizure burden associated with DEEs significantly increases the risk of mortality in particular due to sudden, unexpected death in epilepsy or SUDEP. Within the spectrum of DEEs, SCN2A and 8A-related DEEs standout due to their severity and resistance to treatment. These 2 genetic DEEs are among the most severe, often manifesting from birth or early infancy and resulting in very high mortality rates, with most affected children not surviving into adulthood. Although these conditions are rare, about 2,300, 2A patients and 2,400, 8A patients in the U.S., the unmet medical need is immense. Currently, there are no approved medications, leaving 2A and 8A patients with even fewer treatment options despite their heavier disease burden. These children are typically treated with a combination of antiseizure medications, which offer limited efficacy and often come with significant tolerability issues and complex treatment regimes. It's important to note, the EMBOLD study population was heavily pretreated, so any observed efficacy of relutrigine is in addition to standard of care. But maybe now, let me better introduce relutrigine, also known as PRAX-562. Relutrigine is a sodium channel modulator that was developed at Praxis and represents a novel approach to treating DEEs. Unlike traditional sodium channel blockers, the target channels in their resting states, relutrigine works preferentially on sodium channels in their hyperactivated states. This selective or functional targeting allows relutrigine to reduce pathological sodium channel function such as persistent current without impacting the tonic or resting state current that can lead to tolerability concerns. As a result, relutrigine has the potential to be more potent across multiple sodium channels while avoiding the safety issues that have historically limited the effectiveness of standard sodium channel blockers. Our preclinical studies were highly encouraging. Not only did we observe remarkable efficacy in the MES model with excellent tolerability, leading to a broad therapeutic index, relutrigine achieved complete seizure elimination in 2A and 8A DEE genetic animal models. Additionally, before the EMBOLD study, relutrigine was tested in over 130 human participants across single and multiple ascending dose studies. Together with human exposure data from the EMBOLD trial that Marcio will discuss shortly, our findings suggest that participants and patients are achieving exposures expected to be well within therapeutic ranges as predicted from the animal models. Together, these studies demonstrated a favorable safety profile and significant pharmacodynamic activity in the brain, further supporting our decision to advance relutrigine into safety and efficacy trials. This promising profile across multiple data sets suggest the relutrigine's mechanism of action could benefit patients across a broader range of DEEs, reinforcing our commitment to improve outcomes in this challenging group of disorders. With this scientific background in mind, I will now turn the presentation back over to Marcio, who will walk you through the study design, the key results and their implications for the future of DEE treatment. Thank you.

Thanks, Steve. Let me now discuss in a bit more detail the EMBOLD results. Patients were randomized 1:1 to receive relutrigine or placebo. When assigned to relutrigine, patients stayed for 16 weeks on drug. If assigned for placebo during this period of 16 weeks, they received placebo for 4 weeks and relutrigine for the 12 weeks remaining. After 16 weeks, patients were eligible to continue receiving relutrigine for up to 1 year in the open-label portion of the study, which is still ongoing. This being the first study with the drug, it was important and paramount that we observed the safety in patients. From an efficacy standpoint, we set up to examine the change in frequency of motor seizures between drug and placebo as well as the rates of seizure freedom. We have also examined the overall impression of change in multiple relevant clinical parameters by both the caregivers and clinicians. EMBOLD was blinded not only for the assignment of relutrigine or placebo, but also for the periods during the 16 weeks when patients receive placebo or not. This design allow us for minimization of time on placebo, which is important due to the high seizure burden while maintaining the integrity of the observation. The success of the implementation in this part of EMBOLD encourage us to continue to use the design for the next phase of development, and therefore, we will maintain the assignment periods blinded at this point. Now let's move on to the study disposition. 74 patients prescreened, and of those, 20 were assessed at the study site for eligibility and 16 met the criteria and were randomized in this study. The study enrolled an exclusive pediatric population with confirmed mutations in the SCN2A and SCN8A genes. Patients had to be stable in their dose and regimen of background [indiscernible] for more than a month prior to screening and had a minimum of 8 motor seizures every 4 weeks. The enrolled population mimics the severity of the condition in the real world, with patients presenting with seizures daily and early in life and having a high and unstoppable seizure burden. Enrolled patients have a median of over 50 seizures every 4 weeks, which unfortunately is a reality in this population. From a safety standpoint, relutrigine was generally well tolerated, and the adverse events observed were expected for both the population and the intervention. The most common treatment emergent adverse events while receiving relutrigine were infections, vomiting, pyrexia, somnolence and constipation. AEs were mostly mild to moderate and no drug-related SAE was reported. During the course of this study, patients could reduce the dose of relutrigine in case of tolerability issues to 0.25 milligrams per kilogram per day. No patient was required to dose adjust during the study. Now moving on to efficacy. Patients receiving relutrigine have seen a placebo-adjusted reduction in motor seizures frequency of 46% during the course of the study. These are remarkable results, considering both the severity of the patient population who presented with over 1,700 motor seizures as a group at baseline but also the duration of the treatment. Even more impressive and unexpected was the ability to achieve long periods of seizure freedom by several patients. This is very humbling and it's worth reflecting on the fact that seizure freedom has never been reported in the population before, and it's clearly a meaningful outcome expected by patients and caregivers, which is directly associated with bad outcomes in any epileptic condition. When we isolate the single periods of time where patients were either on placebo or drug, the results are also very dramatic, with 27% median seizure reduction in the month alone paired with a minimum placebo effect, which is expected in this population. 13 patients elected to participate in the long-term open-label part of the study. As of last week, 8 patients on that group had data for at least 28-day periods available to be analyzed. When computing the change from baseline on that population, it's clear the effect we are seeing with a remarkable 75% median reduction in motor seizures. It's worth noting that we see, as expected, an association between general better results, including seizure freedom and exposures, which are expected to be achieved by 1 milligram per kilogram per day. Moving forward, we are initiating all patients in the registrational cohort of EMBOLD at 1 milligram per kilogram per day. While the remarkable reductions in seizures should be more than enough to keep us excited about relutrigine. It's truly meaningful to see gains in several areas observed by both caregivers and physicians, including the positive change in alertness and communication together with notable improvement in seizure severity and intensity. I would like to take a moment to thank all the patients, their caregivers and health care professionals involved in EMBOLD to date. We look forward to continue to working with them and expanding our partnership in this community. With such compelling results, it became our obligation to quickly move the program towards registration. With that in mind, in anticipation of a positive result as we've now seen in EMBOLD, we have planned administrational cohorts comprised of 80 SCN2A and 8A patients. This phase of the study will have sites in Europe and the United States, and we are now officially open for enrollment. We expect this portion of this study to be sufficient to confirm the benefits of relutrigine. We also plan to meet with regulators by the beginning of next year and align our registrational program for the additional 100,000 patients with DEE, who we clearly believe would benefit from relutrigine. I'm now going to open the call for Q&A. Operator?

[Operator Instructions] Our first question coming from the line of Yasmeen Rahimi from Piper Sandler.

Congrats on the data. I think the first question that clients are going to be wondering is, how does this data compare to maybe other current approaches that are in development? Obviously, it's difficult to make an apple-to-apple comparison. But if you could just put it into context of what this data means from a competitive perspective, that would be great. That's question one. And then question two is, maybe you could maybe allude a little bit in regards to your plans into a broader population, like what maybe the steps are necessary to do have to engage with the agency, what would that look like? And how soon could you come back and communicate that with us, that would be really helpful. If we could start on those two, that would be great.

So on the first one, on how it compares, as you rightly said there, I think that you're right, comparison is very difficult. But if you look at face value, as I think we should, when direct comparisons are not possible, there is nothing in developments or there has been a development that comes even close to the results we're showing today. I think it's very important when you analyze data for these studies on such severe population that you answer a number of questions. The one is whether or not the proper population was selected from the study. We know that DEEs are majority pediatric, with the high seizure burden that they were identified properly before. So we check all those boxes for EMBOLD. And quite importantly, right, while we never expect or should never expect a very high placebo effect on this population when you select them properly, that we adjust properly for placebo. And when we look into that, the results we're seeing today are unbeatable, really when you look across the board. So I think that's the not so humble way that I would answer the first question. But then when you take a step further and you're looking to seizure freedom, then we are unaware of anyone who showed anything even close to seizure freedom, and that should not be underestimated. And I'll ask all the parents around this call to put themselves on the other parents' shoes that are taking care of the kids and the kids themselves. But having a long period of time without seizures is incredibly significant. We do -- we run this business for multiple reasons, but the primary is to give relief to people who cannot be in the room having this discussion with us. And I think that's what we are seeing today. On the second part about like how fast and what is the approach for the 100,000 patients or so with DEE that we believe we can address. So two steps, right? So one, we're taking the 2A and 8A out of the way, right? They are starting. We can recruit patients today for the registration for the pivotal study and that is already going. And I think everyone should pay attention to that as well on how forward we are in terms of really executing on those programs. For the larger study, we do believe a regulatory interaction is granted in terms of how we define the population, how it would be treating the population if titration would be the same as we believe it would to 1 milligram per day and the auto titration that we see with relutrigine and obviously, the duration of that study, the size and so on. We don't expect anything unusual, but we're going to be planning an -- we are planning an interaction for early in the year, so we can start the other study right away. As I've mentioned on the prepared remarks, that alone is over $2 billion, and that's why we look forward to explore.

And then Tim, I apologize for sneaking in one last question. Given that you had 8 patients on -- in that 28-day period as well as the longer-term, you had 2 additional. Could you talk about the homogeneity and the response among the small cohort of patients? And I'll jump back in the queue.

Yes. So for the patients in long -- you never into apologize, Yas, for your questions. If you look into the long term, right, we have 8, obviously going to have the remaining of the patients as time goes by between now and the end of the year, it's very homogeneous. We see all patients like with very good response there -- a significant number of them are obviously seizure-free. So there are 100% reduction now and we continue to hope that they're going to stay that way, knowing how severe this disease is. It's a huge feedback. We mentioned on the deck, over 200 days, the longest follow-up we have seizure-free. I think that is absolutely no one you can call any expert after this call that would tell you that was ever possible on this population. So very homogeneous. We know the dose associated with it. We know the titration that is associated with the highest benefit, and we're going to be driving that on the next phase of the program.

Our next question coming from the line Joon Lee with Truist.

Congrats on the strong data. Dr. Petrou's explanation on the functional selectivity of relutrigine was really helpful. And trying to understand how it could be differentiated from other sodium channel inhibitors. So the question is, how prevalent is the off-label use of sodium channel inhibitors for DEE? And -- number one. What would be the washout period for the trials that you have in mind? And does this mean that the trial could, in series, look like a randomized withdrawal And what I mean is that if you are -- if the patient is on stable sodium channel inhibitor and then you wash them out, is that like in essence, a randomized trial -- withdrawal trial?

So the -- for the current study, we allow patients to stay on the background therapy because, obviously, the risk of status and other complications are very high. So we don't see necessarily, from the get go, the needs to remove the drug or to wash. Now for patients that could do that during the study or after the study, as the concentrations of relutrigine increase, there would be an option that it was in the current study as well. I think ultimately, the goal is to have relutrigine being monotherapy for these patients. A cleaner drug with like less general complications, and we know those other drugs are pretty dirty in general. Now to your first part of your question -- and then I'll hand over to Steve to see if he has any comments here as well. For the first part of your question, when you look around the universe of patients that are being treated with DEEs, right, so that are anywhere between 100,000 to 200,000 of those patients that are -- a couple of patients are very different, like the classical loss of function SCN1A patients or the LGS patients, like a subpart of the LGS patients. But outside of the domain -- well, in that domain is about 30%, sodium channel modulation. Outside of that is the #1 therapy that is being given off label. The key limitation is tolerability, like the physicians attempt to increase the dose, and they cannot because they hit the proverbial wall, and therefore, they have to stop. So they never really treat these patients optimally. That is a perfectly priced markets to a drug that is not only better from an efficacy, but also better from a safety perspective in a market that is basically there is no competition, right, there's no one that could show something like this. But maybe Steve, you can talk a little bit about why this mechanism, when you compare it to others in the market or in development, has no limitations.

Yes. Yes, absolutely, Marcio. So it's a great question, Joon. And if you think about it, sodium channels are the gatekeepers of all excitability in the brain. So unlike pretty much any other target, you have to pass through a sodium channel in order to be excitable and in order to have a seizure. Now the issue is it's the manner in which you interact with those sodium channels with a drug that determines the relative efficacy versus the tolerability. And I think it's that challenge that has held back sodium channels from being more effective than they are, and it's a thing that we tackled head on. So that mechanism is central. You can -- there is no AMAX limit as there is with other mechanisms. There is a limit in the actual properties of the drug. And I think that's, in some ways, where Praxis has really differentiated itself from that perspective. And therefore, sodium channels have got a lot of capacity to be used very broadly across the whole range of DEEs.

Fantastic. If I could ask one quick question, follow-up. I was a little shocked that you actually don't wash them off of existing sodium channels. So you're actually thinking that you keep the patients on whatever off-label sodium channel they're on and add on relutrigine, a better sodium channel. Is that -- that's the idea? And so in the trial that you just reported, like how many patients were on baseline sodium channel inhibitor off-label?

Yes. So the majority of the patients had some concentrations. We measure concentrations for all those patients as well, so we know that there were on therapeutic concentrations that they could tolerate. There are clearly suboptimal, right? So looking to the baseline, as I'm sure you're seeing on the deck, we're talking about 2 to 3 motor seizures per day these patients were observing at baseline. Like we're now to the point that we -- I would say, spared more seizures than they had at baseline as a group, like over 2,000. So imagine like as we continue to optimize this drug and actually remove those drugs, as we started to do it on a number of patients already with very good results. It does pose actually ungating events as we allow for that for recruitment in future studies since it's very, very difficult for physicians and for parents to remove the drug that is keeping this patient somewhat stable. So that was a key decision point for us and clearly works, right? I think it proves the point that Steve was just saying. This is a function of selective drug, it's not one more sodium channel blocker.

Next question coming from the line of [ Athena Chin ] with TD Cowen.

First on tolerability, how much dizziness or sedation was seen? And next on efficacy, what was the onset of effect of relutrigine? And how fast did patients achieve that seizure freedom?

Yes. So maybe I'll start with the last, right? So the seizure freedom was associated with concentrations that are around like or higher than about 300 nanograms per ml, and we can easily get to that on the high end of the 0.5 milligram per kilogram per day, but certainly on the low end of the 1 milligram, and that's why we are moving all the patients to one moving forward. Relutrigine is a very long half-life drug so it does take a while like in the beginning to get certain concentration. So in the first few days, you'll really not see therapeutic concentration. But at the start in the second week of treatment, we see a good relationship between the reduction in seizures and the concentration is increasing. So it's not something that takes a very long period of time. And for seizure freedom, it does start after a few months on treatment. That's when we see a more consistence, because I think consistency is quite important here, more consistent effect. And I think that is actually as expected, right? When you look into the preclinical work that we've done, or the clinical work over hundreds I have volunteers that we explore the PK and safety PG relationship for this drug, that's pretty much what we are expecting that will take. So it's good on things lined up in science as well.

Got you. And lastly, what was the severity of somnolence or sedation?

Yes, I am sorry for that, I am yet to address. So it was actually, the incidence was not the high, it was mild. As you've seen paradoxically, we see increase in alertness as well on this cohort of patients. So I think what we are seeing here, it was actually to Joon's previous question, right? They're restacking it up with a number of other medications, you start triggering a little bit the limitation of the other medications as well. So removing them is what we see as the issue, but none of them led to this continuation or to any like more problematic. So everything was mild to moderate.

Our next question coming from the line of Yatin Suneja with Guggenheim.

Let me add my congratulations as well, very nice results. Just a couple from me, mostly clarification ones. How should we think about the placebo response in this patient population? Our understanding is that it tends to be a little bit higher than 2% that you have observed in at least the single -- the 28-day period. So that's one. And then help us understand this low transformational -- transformation estimate that you're using to drive placebo adjusted efficacy at 16 weeks.

Thanks for the question, Yatin. So I think that this is the first time, right, this population is studied properly. So I'm not sure that is a benchmark that we can go and actually look from a placebo perspective. This is -- through all the preparations for the study, when you're talking to key opinion leaders and to parents, we heard again and again, right, those patients stay pretty constant. They have a little bit of variability throughout the month, but that shouldn't be an expectation of placebo. And I think what we're seeing is similar to that. There is some variability coming in on the study and enduring. But it's by no means anything exaggerated in terms of placebo. So I think it's as expected. If you go back to previous conversations, we had a webcast and other calls, we also talked about, those are intractable. This is not your -- I don't want to minimize that, but run of the mill, DEE, where you see a lot of the patients spontaneously getting better throughout like a short period of time. We don't see this as incredibly severe patients. So we're not expecting placebo effect, and that's what we're seeing. As far as the log transformation, I think that is another -- maybe I'm going to use run of the mill again, right? You're looking to virtually every drug that's been approved in epilepsy end up with a non-normal baseline, right, the distribution like is not fitting, like the methods are, if you look into, it's 1,000 seizures and the other one is like 15 seizures. So in order to do a proper correction, we try to bring them to the same space. And the way to do that, the most simple way, the most acceptable way is looking to both [indiscernible] studies, for example. That was the primary analysis, exactly the way we're doing. You bring them to the same space and then we can compare that. So nothing unusual there either, just like trying to normalize the patients so we can compare them better.

Got it. Very helpful. Very helpful, I think, explanation. One more question, if I may. This is a specific question that just came from an investor. Could you just talk about your approach to DEE? Because our understanding is that sodium channel blockers are contradicted for some populations like Dravet. So how would you be able to go after broader DEE? Would you just not go after certain indication where the sodium channels are counter-indicated? Just curious to understand the dynamic, how it plays out from the regulatory and development standpoint.

Yes. No, absolutely. So that is, again, 150,000, 170,000 are DEE patients outside of Dravet, right? So maybe we start with that. I think that is a general obsession with this one indication because there is a lot of approved drugs. They work pretty well and people are filing on approved drugs. But the -- it's actually not counter-indicated, like first generation, second generation should not be used because of like pretty bad multichannel effect that they have. So maybe just go back to the science there on anyone that looked. Actually, the bar for counter-indication is very high and people use that term very liberally, but it's not where we would start, mostly because there's a number of drugs that work pretty well for that patient population. We don't see the unmet needs on the remaining 100,000 patients that there isn't anything, whether or not it's a 5-HT mechanism or something else that wouldn't work for those patients. And our sodium channel does work, it just has very, very severe limitations right now and we're removing those limitations. So for whatever markets that we think SCN1A loss of function, which should be Dravet, but it's a little bit extended from that, is you can multiply that by 10, and that should be the market for DEEs that can be addressed with sodium channel modulators. So there is no need to talk about the small part of the market that is already fulfilled.

Our next question coming from the line of Douglas Tsao with H.C. Wainwright.

Congrats on the results. Maybe, Marcio, I think it would be helpful. I'd just be curious to get your thoughts how you're thinking about 562 in the context of SCN8A versus elsunersen, where we also got some very impressive results. I mean, how do you see the 2 therapies sort of sitting next to each other in the market? Who would you -- do you think one would be sort of the initial treatment versus 562?

Doug, so if you break down our approach for relutrigine to DEEs in general. So one is the SCN2A and 8A, and I want to keep bringing us back, 8A is a huge unmet need as well. And that's pretty straightforward, right. No one really doing anything and/or any registration [indiscernible] now. For 2A, it's not that different in a sense that we believe the needs are complementary here. One could imagine like in a few years that you would have a maintenance treatment with PRAX-222 and like a control on top of that of sporadic seizures and so on with 562 or relutrigine. So very complementary. There are other space, and I'm sure you can think about more than I can right now, what you have this duality of 2 mechanisms actually regarding the maximum out of a disease. And that's how we are looking to this. And I agree with you. the results with 222 are equally impressive than they are here today. So it's good to be in a situation that we can help patients multiple ways. But as we move forward, really focusing on these larger DEE markets as well, which is above many more patients, thousands and thousands of patients without approved adequate treatment, also from a market opportunity perspective, I think brings the ability for us to continue to develop these drugs for other patients with DEE.

And if I can follow-up. So obviously, I think everybody is initially going to focus on the seizure reduction numbers, which are really impressive. But when we think about the potential of the drug, I think, what seems very compelling is sort of the other benefits that we saw in terms of patient sort of verbalization and awareness, et cetera. Just maybe if you could provide some context how that compares to other treatments on the market and the standard of care in terms of the rates of improvement that you saw with relutrigine in EMBOLD?

It's like it doesn't compare, right? Because if you look into the rest of the market, unfortunately, may I say they actually add to already a very severe disease. They reduce alertness, they reduce communication. They reduce -- they oftentimes increase the severity of seizures. When the therapeutic levels are lower, they have to be given multiple times a day for that not to happen. There is no, right now, in development or off-label in the markets that seeing the consistent improvement in alertness, in communication, reduction in disruptive behavior that you've seen with relutrigine. It was actually quite cool as well when we are analyzing the data that you've seen both the assessment by the caregiver and the physician to be almost identical, right? Those are independent assessments done at like completely different settings and mindsets. And when you look into that being consistent, like we truly believe that these patients are doing significantly better. As we're reviewing the data with the principal investigators over the weekends, I think what we heard from them was this is exactly what we're seeing in our patients. And it's very unusual to actually see people who are excited about participating in the next phase of development because they were not expecting to see patients doing so well, and they are doing that well. So yes, we shouldn't minimize, and I appreciate the call out for us not to minimize that impact.

Our next question coming from the line François Brisebois with Oppenheimer.

Congrats on the data. I was just wondering, in terms of the specificity here and the strategy behind the prespecified -- prescreened patients, the 74, and then 21 and the eligibility of 16. Can you help us understand what goes in to that? Just making sure that you have the right patients. And why from going to the prescreen number to ultimately the 16, why -- what is so restrictive? And how does that translate into the market down the road? And then I'll have a follow-up.

So I think they-- I'm going to call that Praxis is special, right? And maybe, another underappreciated aspect of what we do. When people often ask us like how can you enroll this study like faster to company Y, Z, W, 5x, 6x what you are doing. And we do actually conduct a lot of the prescreening ourselves. And by prescreening, what I mean here -- like most companies would not even show you those numbers, right, because they wouldn't have those numbers. They wouldn't be done in-house. And what we mean by that is like geographic location abilities to be on the site or ability to participate in the study. Are they stable on a dose of the medication? A number of things, right, that you can imagine, they couldn't have status of 3 months before getting to this study, which unfortunately is pretty common. So it wouldn't be able to hear. So I think that number, what you see is really the ability, and I would say, the Praxis machine at work on actually getting to know these patients, and I can't thank enough my team to actually being able to do that so diligently every single day. It's not that different than what you do with potential tremor with thousands and thousands of patients being prescreened, right? So that is the same. When you look into actual, what is normally what people talk more that between the 21 and actually patients being randomized, I think it's your typical patients who were unfortunately had to use another medication during the screening process so they are no longer eligible or they had to be hospitalized or something like that. So nothing unusual there. I think those are more the usual rates that you see throughout. I think what you're going to see moving forward and we're already hearing from, if you look into our press release, we had a joint statement from all the major patient organizations, and what they told us is this open up to a lot more patients that are really available in the U.S., but they were not willing to participate on the first study, right? And now people are willing to participate on a second and third study and things like that. So all in all, I think it bodes incredibly well and show, one, our level of transparency, but zero level of diligence.

That's very helpful. And then in terms of the read-throughs, are these patients -- in terms of DEE, are these maybe the hardest patients, the worst? Or are they all -- they all have their difficulties regardless of the population? Or is it like, look, we got an SCN2A and 8A, so the odds that this is working in other DEEs is actually a lot stronger because this was a very high bar. And then maybe if you can touch on the read through to 628 as well.

Yes. So I would say we've been pretty consistent about this, right? Those are the hardest patients. I think if you ask around like 2 key opinion leaders look into these patients, one of the key limitations of the study, a lot of them couldn't leave their house because like the travel alone would be so disruptive for treatment. So you can imagine that. I would say on one side of the spectrum, you have those patients, on the other side of the spectrum, you have like the older patients that people still call as DEE, but they are like on their teens or older, that they are a lot more stable and they are arguably easier. So as we move from this incredibly severe patients to a larger population, one could argue that the bar actually lowers, meaning it's easier to treat them. Now, every seizure matter, every patient matter, I'm not trying to whatsoever to minimize the severity of a single motor seizure because those things are incredibly disruptive. They lead to SUDEP, they lead to death. So we should never try to compare patients. For that patient, that seizure is very important, but evolves incredibly well from a [indiscernible] of success. Now to the second part of your question, right, how does it look into 628? Well, imagine what you can -- like you can achieve on a disease that is less severe, that is less complex, that is for [indiscernible] seizure. Because these channels and the brain is not "on fire 24/7." It's not hyperexcitable like the entire day. It's not firing like crazy, it sporadically does. And the drug being available, which is the important thing at therapeutic levels that are around the same that we have here, that bodes incredibly well, endless this part of the conversation works like a comparison. What we see seizure freedom with relutrigine around over 300 nanograms per ml. So that is about 3x the MES [indiscernible] relutrigine. We are starting to dose patients with 628 at about double to more of that. So you can imagine what can happen, right? Should we close our eyes and imagine a situation where like seizure freedom would be the norm on treatment moving forward after 628? I think we've got to give ourselves the [indiscernible] today based on these results. But go back to work and look into what we need to deliver that is a very solid, like best-in-class, best-ever result for 628 as well, and that's what we're expecting next year.

Our next question coming from the line of Ami Fadia with Needham.

Congrats on the strong data. A couple of questions just with regard to how we should think about some of the sort of design elements as you think about the registration study. How could sort of the efficacy results differ if you initiated all patients on 1 milligram per kg? And looking at Slide 17 and 18, where we sort of see -- on Slide 18, response rates from patients who dosed up during the double-blind period. So should we anticipate an improvement in response rates if all patients started at a higher dose? And how should we think about impact should patients not have other sodium channel blockers on board at baseline? If you could sort of help us think through that and then I have another question.

Yes. So Ami, I think everything we know right now that is a good dose response between 0.5 and 1 milligram, or maybe I should say, there's a good exposure response, right, because at the end of the day, that's what matters, it's the exposure we're getting. And it's a positive trend as we increase the dose to 1. So when you go back and you start those patients and give them more opportunities to be at those exposures, we can only imagine the results to be more consistent and potentially better. So that's how I would imagine that. Now on patients not being on sodium channel blockers at baseline, I think for SCN2A and 8A on the registrational cohorts that we are running right now, it's going to be a very rare for that to happen just because those patients are often treated. So they would be able to remove that during the trial as well as possible during this study same in like 25% increments on the reduction after a given point in time, but not starting. I don't -- I can't see how that would be possible with the risk of status and the risk of that being so high on this patient population, right? Now for the larger DEE population, which I think we're going to have like a significant number, what we would see, and we believe based on one -- at least one patient that we know could not tolerate any other sodium channel blocker and that were in our study, I think what you would see is what you expected, but this mechanism works. I think it's known that it works. So the question is whether or not they can't get to therapeutic levels and they can tolerate, which today is a great step towards that. So we expect them to do really well on 5, 6 years less relutrigine. So we don't see a limitation there, potentially even being able to get faster to better resolution of seizures because there is no other things impeding them to get to that point. But I think for today, we just celebrate the amazing results and continue to plan as we move forward.

Great. Just one more question, if I may. As you think about a broader clinical development in other DEEs, you talked a little bit about Dravet syndrome. But outside of Dravet syndrome, should we assume that you would think about a trial in all DEEs other than DS? Or would you sort of -- is that what that you're going to do to sort of identify with specific DEE subtypes would be more suitable?

Yes. So I mean, the way we look into this, very extensive research both on use of drugs like seizure rates, like effectiveness, tolerability, you name it, right? So I think what we are lending right now, and that's the discussion we want to have as well as regulators, is phenotypically driven versus a genotypically driven DEE treatments. And what I mean by that is high seizure burden not being able to control, they would be eligible to be on this study and we would outreach them. So it's kind of all -- is the all category that you just mentioned.

And our next question coming from the line of Joel Beatty with Baird.

Congrats on the data. First question is, how much reducing or removing of other medications did you see over the course of the study or in the long-term extension?

Yes. We're just seeing on the long term, Joel. So during the study, actually, we haven't seen that happening. So I think there was a caution from the investigators and the parents as well on keeping things stable. As things are going well, I think people tend to want to keep them reasonably stable. And now in the long-term extension of seeing people being a little bit more adventurous in terms of reducing the side effect by removing those toxic background medications.

Okay. And then can you provide any more details on the one patient in the placebo group who is now eligible for the efficacy assessments, and why that was?

Yes. So that patient was here in the U.S. and could not comply with study procedures. So it could not be assessed, basically, there was no data in the diary. No evidence that the drug was being taken. So that's why it could not be assessed.

Got it. And then maybe one more follow-up. Can you provide any context on what type of enrollment speed to expect in the study that's just starting now compared to the study that is reading out?

Yes. So we were able to enroll this study, I would say, from effectiveness perspective, give or take, in about 3 quarters. Obviously, what the pace, we only had 2 sites in the U.S., one site in Europe. So there -- and obviously, it was a hybrid approach as well. We could send a medical team to their house as we're going to continue doing. As we move forward, we're going to keep those sites. They did a phenomenal job, and they're going to continue to work with us, but we are expanding as well quite significantly, right, for our scale quite significantly, for other people's scale, it's still going to be a small number of sites. So we think we can deliver on about, I would say, no promise right now. We need to get off the ground, but probably about the same time to give or take like a quarter or two there. So our goal is really to get this drug submitted by 2026 to the FDA and get a market authorization in the [indiscernible] outside that year. So we're marching towards that. We pretty strongly believe that with all the support we're getting from the patient groups, from the physicians in general, that's possible, but early days. So we need to work hard on that.

And our next question coming from the line of Kambiz Yazdi with Jefferies.

Congratulations. And maybe just following up on kind of the breadth of the program. What you consider development in nonsodium channel DEEs, you saw some kind of anticonvulsion activity in some PTZ-induced preclinical seizure models. So I just wanted to get your perspective there.

Yes, yes, absolutely. We look at this drug across PTZ, we look at it across MES. We look at it across other genetic epilepsies. We see efficacy, and it was back to the reason that we discussed with Joon earlier that all of these mechanisms all converge upon the axon initial segment, where a part of the neuron where the sodium channels are in very, very high concentration to determine the excitability. Because they all have to pass through that node, they're all going to be subject to a mechanism that can interact with the sodium channels at that target. So we do see a lot of potential outside of etiologies beyond sodium channels for this disorder, and we got enough evidence I think preclinically to show that that's trending in the right direction for sure.

Ladies and gentlemen, that's all the time we have for the Q&A session. I will now turn the call back over to Marcio De'Souza for any closing remarks.

Thank you very much. Thanks for being in the call today. But I would say my real big thanks goes to the patients that participate on this study. We definitely wouldn't be here without them. It's exciting times for us. It comes with great responsibility, every time we have a drug that works this well, and it's twofold. One is to make sure we don't screw up and then we actually get this done, and we are very diligent. And the second, what I would say is for the team at Praxis. They put all the energy and all their hearts towards getting today's results. So definitively onwards and upwards in terms of where we are. We're going to enroll this study quickly. We're going to get this drug submitted and our commitment is really to help these patients and to get like everyone in a much better state than they are today. So thanks for joining. I'm sure we're going to have a lot of follow-up calls and appreciate the support as well. Take care.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.