Good afternoon, and welcome to Supernus Pharmaceuticals' conference call to discuss the planned interim analysis of the exploratory open-label Phase IIa study of SPN-817 for treatment-resistant seizures. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. As a reminder, this conference is being recorded. I would now like to turn the conference over to Peter Vozzo of ICR Westwicke, investor relations representative for Supernus Pharmaceuticals. You may begin. Thank you, Lisa. Good afternoon, everyone, and thank you for joining us today for Supernus Pharmaceuticals' conference call to discuss the planned interim analysis of the exploratory open-label Phase IIa clinical study of SPN-817 for treatment-resistant epilepsy. Today, after the close of the market, the company issued a press release announcing these interim results. On the call with me today are Jack Khattar, Supernus' Chief Executive Officer, and Jonathan Rubin, Senior Vice President, Research and Development, and Chief Medical Officer. Today's call is being made available via the investor relations section of the company's website at ir.supernus.com. During the course of this call, management may make certain forward-looking statements regarding future events and the company's future performance. These forward-looking statements reflect Supernus' current perspective on existing trends and information, including the company's reporting on preliminary and partial interim data from the exploratory open label clinical study of SPN-817. Any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, including those noted in the Risk Factors section of the company's latest SEC filings. Actual results may differ materially from those projected in these forward-looking statements. For the benefit of those of you who may be listening to the replay, this call is being held and recorded on May 23, 2024. Since then, the company may have made additional announcements related to the topics discussed. Please reference the company's most recent press releases and company filings with the SEC. Supernus declines any obligation to update these forward-looking statements, except as required by applicable securities laws. I will now turn the call over to Jack. Thank you, Peter, and good afternoon, everyone, and thanks so much for joining us on this call. I would like to start first, following the slide sequence by slide 4, with an introduction and agenda, covering an executive summary as to what the data briefly sees and mentions, SPN-817 overview, and then I will transition over to Dr. Rubin to walk you through the study design for the Phase IIa study and the interim results. Then I'll come back and talk about the conclusions of the data. Starting with slide 5 on the executive summary, the emerging profile of SPN-817 suggests that we have a highly differentiated anti-seizure product candidate for focal seizures. Briefly, when it comes to efficacy, the product seems to exhibit strong efficacy across several measures, as you will see in the next few minutes as we present the data across so many different metrics. In addition to that, the product seems to have high responder rates and a higher efficacy in more severe patients. So consistently across several measures, the efficacy story seems to be evolving and emerging as a potent, effective anti-seizure product. In addition to all that, in an area which is very important in epilepsy, cognitive improvement, the product seems to also show a potential for cognitive improvement. Regarding safety, the product is safe, and it has a competitive and acceptable tolerability profile. And finally, the product also represents a novel and unique mechanism of action for epilepsy, an area which we covered briefly at our R&D day back in October of 2023. So as a quick reminder on slide 6, you'll see that that mechanism of action is fairly unique. As far as we are aware, this is the only acetylcholinesterase inhibitor that is in development for focal seizures currently. Huperzine A, which is the drug in SPN-817, is a potent and selective acetylcholinesterase inhibitor. It is an enzyme that metabolizes acetylcholine, and by inhibiting this enzyme, you basically increase the extracellular levels of acetylcholine. Higher levels of acetylcholine activate the cholinergic pathways in different cell types in the brain, and that, we believe, ends up restoring the excitatory and inhibitory balance, which is important for seizure control. In addition to that, we have also shared with you at one point back in October of 2023, that we have significant data on this molecule showing the anti-seizure effect in different seizure models and genetic models of epilepsy. With that, now, I will transfer it over to Dr. Rubin to take you through the Phase IIa study. Thanks, Jack. So I'd like to start talking about the Phase IIa study design. This is an ongoing study. It's a Phase IIa, open label, flexible dose, safety and tolerability exploratory study. The study enrolled 41 adult subjects with treatment-resistant seizures. And in terms of the inclusion criteria, we included subjects who had at least 4 motor seizures during screening. This was assessed during the screening period with a 42-day baseline seizure diary that was normalized to a 28-day period, which is standard in clinical trials with seizures. When we did this, we saw that the median baseline seizure frequency was 11.3. In addition, we included subjects who took at least one concomitant anti-seizure medication or ASM. This was an adjunctive trial. There was no upper limit on the amount of anti-seizure medications that they could take. And the average number of concomitant anti-seizure medications was 3.4, with a range of 1-6. It's important to note that other clinical trials of seizures typically will set an upper maximum of either 3 or 4 anti-seizure medications. With these two inclusion criteria, we included patients who had intractable seizures, whose seizures were not well controlled and were more severe. As I mentioned, the study is ongoing and is being conducted in 8 sites in Australia. SPN-817 is being given orally and twice daily during the study, starting out at 0.25 milligrams BID or twice daily, and can be titrated up to 4.0 milligrams twice a day. In terms of the conduct of the study, there was a screening period of 8 weeks during which the baseline seizure diary was included, and then onto a dose titration optimization period of roughly 8 weeks, and then to a maintenance period of 12 weeks. For those who got through the maintenance period, they had an optional open-label extension period of up to 52 weeks, or they could be tapered off the drug over a 4-week period. I'm now going to go to Slide 8. So in this study, the primary assessment was safety. It's an open-label study. We looked at adverse events, and specifically, we looked at adverse events leading to discontinuation. We also looked at efficacy, a variety of efficacy measures, and the key secondary or primary efficacy analysis was the percent change from baseline and the quantifiable motor seizure frequency for 28 days through maintenance and also during the open-label extension period. This analysis is standard for seizure studies. We also looked at treatment response at a 30%, 50%, and 75% reduction in median seizure frequency. And we looked at the Clinical Global Impression of Severity, or CGI-S scores, as well as EpiTrack. EpiTrack is a cognitive screening tool that was designed for patients with epilepsy to look at the cognitive effects of anti-seizure medication. I'm now going to go to Slide 9. So in terms of the current disposition, this is a data cutoff as of May first. And again, I want to remind the audience that this is an ongoing study. 41 subjects were enrolled into the safety population. They received at least one dose of 817. 9 subjects discontinued during the titration period, or 22%, and 2 subjects discontinued because of lack of efficacy, and 2 subjects discontinued related to just withdrawal. They didn't want to be in the study anymore. During the maintenance period, 1 subject discontinued related to an adverse event, and 1 subject discontinued related to lack of efficacy. Now I'm going to go to Slide 10. In terms of the overall summary of safety and tolerability, during the titration period, 95% or most subjects had at least one treatment-related adverse event, TEAE, and 1 subject had a treatment-related serious AE. The details of that event are in the footnote at the bottom, dizziness and nausea that occurred early during the study and resolved. In terms of the severity of the TEAE, there were 18 subjects had a mild AE, or 43%, and 21 subjects had a moderate AE during titration, or about half. There were no severe AEs during titration or maintenance during the study, and there were no deaths. We can see just globally, if we compare the titration column and the maintenance column, that the... Looking at severity, the severity dropped off when we got to the maintenance period. This is related to two aspects, which will be evident in the next slide as well. One is that people dropped because of adverse events, so there's a selection component to that. But in addition to that, and consistent with acetylcholinesterase inhibitors, people who stayed on the drug, even if they had AEs, became tolerant to the effects of the drug. Now I'm on slide 11. So if we look at the individual adverse events that occurred during the study so far, again, we see 95% of subjects had at least one TEAE during titration. The most common side effect, almost half, had nausea, and we also saw diarrhea, headache, dizziness, decreased appetite, and there were 5 subjects who had vomiting during titration. Again, the numbers and the percents decreased during the maintenance period. Now, the protocol allows for the concomitant use of antiemetics during the study to treat and prevent both nausea and vomiting. Actually, during the study, we sent out an administrative memo to the investigators: "Hey, you need to use this as needed to help manage nausea and vomiting." But despite this being included in the protocol and reminding the investigators, only seven subjects were given an antiemetic during the study. This has important consequences, which we'll get to later. Now I'm going to slide 12. So in terms of efficacy, looking at subjects of all seizure types across all doses, this is the full analysis set of subjects who had at least one measurement of seizure reduction, 14 days post-baseline. We see that in terms of the median improvement or median reduction in seizures, we look at the maintenance group, N equals 19 in that group. There was a 54% overall median reduction, which is quite good. It drops a little bit during the open-label extension to 37%. Now, going to slide 13, now we're just going to focus on the focal seizure population. The focal seizure population is the population that we will be taking forward in our planned Phase IIb study. You can see that there were 3 subjects who had generalized tonic-clonic seizures, so the sample size went from 19 to 16 here in maintenance, and from 11 to 8 in the open-label extension. The median reduction in seizures slightly increased, but roughly consistent, 58% in maintenance and 38% in the open-label extension. Going to slide 14. If we look at the focal seizure population by the maximal dose, we see that in the 3 mg-4 mg BID category, where there were 6 subjects in maintenance and 3 in open-label extension, we got to a 75%-86% reduction in the seizure frequency, which is quite striking. But even in the subjects who were at less than 3 mg BID, they still had a 52% reduction. So there are two things that we can take away from this slide. One is, even though this is a flexible dose study, which is not designed to evaluate dose response, there's a suggestion here that if you can get to the 3-4 mg BID dose, you're going to get a much stronger response. But in addition, we see that 10 subjects were not able to get to the 3-4 milligram BID category, and we believe that if with more aggressive use of antiemetics to get to a higher tolerated dose, that perhaps we could get an even higher response, for some of those 10 subjects. In looking at the response rate, again, in the focal seizure population, first looking at the maintenance category, we saw that 13 or 16 or 81% had a relatively decent response, greater than or equal to 30%. But if you look at a 50% response rate, we see 63% of the group had greater than or equal to 50% response. That is a competitive profile, both within approved seizure drugs as well as drugs that are in the pipeline. 3 out of 16, or 19%, had a greater than or equal to 75% in the maintenance phase. If we look at the open label extension phase in the second row, we see the numbers are relatively similar, although slightly smaller for the greater than a 50% response. Now, we did not specifically tabulate seizure freedom in the table, but if you see the call-out box in the right, the green box, there was one subject who achieved 91% seizure reduction during the overall open label extension, and that subject has been seizure-free or having zero seizures, 100% reduction, for the most recent 7 weeks. Another subject has achieved 86% reduction in the open label extension, so that subject is getting close. For the subjects, the 3 subjects who were in the maintenance phase, there's 1 subject who had a very high response in the maintenance phase, who is just entering into the open-label extension, so we don't have information yet, but we will share that later. We're going to slide 16. So now we can analyze the data in a variety of ways. One is we can look by baseline seizure frequency. As I mentioned at the outset, the median baseline seizure frequency was 11.3 seizures. So we can look at people who were above the median in terms of the baseline or below the median. We see for the people who were above the median, people who had pretty significant baseline amount of seizures, a 74% reduction for the maintenance group and 86% for the open-label extension. For those who had a lower than the median frequency of seizures, 50% reduction for the maintenance phase, slightly lower, 23%, for the open-label extension. Now I'm going to go to slide 17.... analyze that a different way, looking at the amount of anti-seizure medications at baseline. So just focusing on the group of subjects who had greater than or equal to 3 anti-seizure medications at baseline, an intractable population, we had a really nice response here, 70% during the maintenance phase with 11 subjects and 60% during the open-label extension with 5 subjects. If we look at the response rate in the same group, so it's the group who had focal seizures, who are on 3 or more anti-seizure medications at baseline. We see all of them, 11 out of 11 during the maintenance phase, had a greater than or equal to 30% response. This response continued in 5 out of 5, or all of them, during the open-label extension. A, a pretty strong response in a group that, has intractable seizures. And we see also in the greater than or equal to 50% response range, 9 out of 11 or 82%, had a response, and 3 out of 5 or 60% in the open-label extension had a response. And then going to the last column, greater than or equal to 75%, 3 out of 11 or 27% had a greater than or equal to 75% response. And in the open-label extension, 2 out of 5 or 40% had this level of response. Now, looking at other secondary outcomes. So we looked at the CGI severity or CGI-S score. We had 16 subjects who had baseline and end of maintenance scores. Baseline was 3.4, and the end of maintenance had a mean of 2.7. This is a drop of -0.8, and lowering the CGI severity is an area that's the direction of improvement. For an individual, a drop of 1.0 is considered significant, and for a group, a drop of -0.8 would be a good reduction in CGI-S score. In addition to the CGI-S, we looked at the EpiTrack, which is an assessment of cognition. We had 12 subjects that had baseline measurement and end of maintenance measurement. Mean baseline score went from 28.7 to 30.9, an improvement of 2.3. Now, in looking at the EpiTrack assessment and looking at improvement, 10 out of 12 or 83% of the subjects were improved or unchanged in terms of their assessment of cognition, and 5 out of 12 or 42% were improved. And notably, three subjects improved from significantly impaired cognition at baseline, which is an EpiTrack score of less than or equal to 28, to average cognition, which is a score in the range of 32-38 at the end of maintenance. Now, I'd like to pass it along to Jack. Thank you, Jonathan. So, to conclude, what the data really mean, we're going to slide 20 on the conclusions. First, starting with the safety and tolerability. As we just reported, most of the treatment-emergent AEs occurred, as you can see during the titration. And as Jonathan mentioned, as expected, a lot of these cholinergic side effects obviously were expected with a class of drug like this and are the most common ones that we saw in the study so far. In the maintenance period, which was extremely important to note, that once the patients were able to transition to the maintenance period, those who did, we had a fairly low discontinuation rate because of AEs, which is only 2.4%. So discontinuations during the titration are something that we will be focused on moving forward, and we believe we can manage that going forward with a much more structured and fixed or about a short period of antiemetic use. Make sure that the investigators actually use the antiemetics as instructed during the titration period. Moving on to efficacy. To wrap it up, basically, the data, as you saw across several measures, seems to have a very consistent trend, and it's showing a very consistent direction. It's showing a drug that actually is potent, where we saw strong efficacy and focal seizures with patients who were able to reach the dose of three to four milligrams, which we believe is the dose range, where this drug can be very effective for a lot of patients, given twice daily. 75% median seizure reduction in the maintenance period and 86% median seizure reduction in the open-label extension. In addition to that, across all the doses, not just the 3 mg-4 mg, but even across all the doses, even the lower doses, you see very high responder rates. In the maintenance period, 81% of subjects had 30% response or more seizure reduction, 63% of subjects had the 50% or more, and then 19% of subjects had 75% or more, focal seizure reduction. Moving on to slide 21. Again, very consistent data. If you look at subjects that had 3 or more other concomitant, anti-epileptic medications, 70% reduction is the, which was the median focal seizure reduction in the maintenance period and 60% in the open-label extension. Again, looking at the responder rates, very strong, striking data as far as the responder rates and subjects across all doses, not just with three or anti-seizure medications. 100% of the subjects had 30% or more seizure reduction, 82%, 50% or more, and then 27% that have 75% or more focal seizure reduction. And of course, we also touched on the two patients who are in the open label. One of them is seizure-free, and the other one is fairly close to seizure-free in the 86% seizure reduction. As far as the median focal seizure reduction in more severe patients, you know, using this time, looking at the 11.3 mean baseline number for patients who were higher than that, again, consistent with the above data, 74% in the maintenance period and 86% in the open-label extension. Then finally, looking at all the subjects that had focal seizure, which is 16 subjects across all the doses, not just the 3-4 milligram, even the low doses, a fairly good level, strong level of 58% reduction in the maintenance period and 38% in the open-label extension. Then finally, on slide 22, we look at the cognitive improvement, as Jonathan mentioned, you know, using the EpiTrack, which is a very standard screening tool, which is also validated. In these situations, 83% of subjects basically equally split between improved or unchanged at the end of maintenance period. One thing I will mention very briefly here, I mean, to be unchanged in this patient population from a cognitive perspective is also potentially a very positive thing. Because typically these patients, especially those who have these intractable or refractory patients, they tend to continue to have cognitive decline as time goes on and as they continue to take more and more medications. So to have unchanged and improved around 83%, we think at this point, as early as this data is, is really very encouraging for us to see. So finally, as far as the plan forward, moving forward, we are looking at extending the open-label study that is still ongoing, as Jonathan mentioned, to assess approaches to mitigate the typical cholinergic AEs that we talked about. We continue to expect the full results of the Phase IIa study, excluding, of course, the recent extension in the second half of this year. Finally, the initiation of the Phase IIb study continues to be on track by year-end of this year. With that, I'll turn it over back to the conference for the Q&A. Thank you. If you would like to ask a question, please press star one one on your telephone. You will then hear an automated message advising your hand is raised. If you would like to remove yourself from the queue, please press star one one again. We also ask that you wait for your name and company to be announced before you proceed with your question. One moment while we compile the Q&A roster. The first question that we have for today is coming from Andrew Tsai of Jefferies. Your line is open. Hi, Jack and team. Good afternoon. Thanks for taking my questions and appreciate the data. Congrats. So the first question is, can you confirm if you have any data or if you've tabulated seizure freedom rates for all 16 focal epilepsy patients completing the maintenance across all doses? And do you have seizure freedom rates for the subset of patients who did make it to the 3-4 mg dose? Yeah. Hi, Andrew. Yeah, I mean, basically, if you look back to on slide 15, you know, where we report, you know, the response rate and the box, which we talk about being two patients, right? So these are two patients out of eight in the open label, so it looks like about 25%. Or the other way around, also looking at it, it's two out of 16, right, who are in the maintenance. So two out of all 16 subjects with focal seizures in the maintenance. Two of them right now, at this point, there could be later more, or it could be less as time goes on. So that would be 12.5%. So it's basically between 12.5%-25% seizure freedom, more or less. I mean, I'll ask Jonathan if he has a different perspective, but that's at least what the data seems to suggest at this point. Yeah, that's right. But I just wanna mention a slight change in that the seizure freedom was obtained during the open-label extension, on the one subject. Yeah. But you got it right. Yeah. But it's out of the total 16 in question, Andrew. Yeah. Right. Okay. And could it make sense to enroll more patients in this Phase IIa, just to make sure you have... You've locked in the titration schedule, as to make sure the use of antiemetics will mitigate the AEs, and you know, basically to confirm patients can get to the 3-4 mg range, or are you at this juncture definitely committed to starting up the Phase IIb? Thanks. Yeah, it's yes to both. So we are definitely committed to, as I mentioned, extending the Phase IIa, the current Phase IIa, to explore a couple things, not just antiemetic use. We have other ideas that we would like to explore. Since we have the study open, we're going to enroll more patients, and it is in patients, which is also good instead of healthy volunteers, and look at a couple other concepts or ideas that we're looking at. And we're gonna do that as quickly as we can, of course. As we're doing that, we will continue to plan and continue to, you know, move forward with the plan to initiate the Phase IIb before year-end. Now, as we do in parallel these two efforts, so anything, you know, great that we learn with the new extension of the Phase IIa, we can, you know, easily incorporate into the Phase IIb. Even if it had started, you know, we can make amendments to the protocol, obviously. Because also the Phase IIb study by nature is a dose-finding, you know, study. It's not a Phase III study, obviously. So we have that flexibility, and that's what the plan is at this point. Makes sense. And then, thank you. And then my last question is, just out of curiosity, based on this data set, efficacy, safety profile, are there any approved epilepsy drugs you think 817 is more similar to in terms of the drug profile? Or are there-- and are there any approved epilepsy drugs do you think 817 already has a drug profile? Thank you. Yeah, I mean, as we all know, and everybody, it's always very hard to compare drugs and trials and, and obviously, everybody reports data differently, and they have different inclusion, exclusion criteria, and so forth. So with that caveat, clearly, it's very important, you know, to watch when we're comparing data. Even just to give you an example, I mean, seizure freedom, we are defining seizure freedom as purely what it means, seizure freedom, meaning zero seizures, right? Other people report seizure freedom, where they may allow, you know, it's maybe one seizure or two seizures or whatever in six months. There's so many different definitions of seizure freedom. So I would always caution people when they try to compare neck to neck. But I can tell you, I mean, we've been in this space for a long time. The levels we're seeing here are pretty striking. Again, early data, not a huge sample size so far, but I mean, the levels of responder rate, I mean, to have a 100% response rate, 11 out of 11, so the end is not really too small, but it's still 11 out of 11 patients with a 100% response, with a seizure reduction of 30%-50%. That is pretty huge, as far as, you know, as far as, you know, the strength of this product or what it seems like, and the potency of the product and so forth, and the consistency of the data across different sub-analyses that, you know, we went through today. So that's really all I can say. I mean, I, I'm sure different people have different things, and they report on different things in the public domain, but I think 100% is a 100%, right? So you can't get any better than that. But, clearly, that's a very strong report. And even across the other measures, somewhere in the 74-86 or 84-85, 74-85, I mean, all of these are very strong levels of median seizure reduction, and what I believe are fairly competitive, very competitive, you know, versus what we've seen from other companies at this point. Makes sense. Thank you so much. Congrats. Sure. Thank you. One moment for the next question. And our next question will be coming from David Amsellem of Piper Sandler. Your line is open. Hey, thanks. So just a couple from me. So you mentioned in the press release that you're focused on optimizing the synthesis process of the synthetic drug and also developing a novel dosage form. So I'm wondering if you can elaborate on that and how that fits in to the advancement of the program. So that's number one. And then number two is, as you think about tolerability, can you talk about the extent to which these AEs attenuated over time as patients passed through the maintenance period? Were these mainly just short-term issues with the titration, and then they attenuated, or were there other things to consider? And then the last question I have is regarding the nausea and the use of antiemetics. Can you talk about that, how that's gonna play commercially? It does that render the product perhaps, you know, commercially challenged if in practice there is a need for significant antiemetic use upon the initiation of therapy? Just talk about how you think that's gonna play commercially. Thank you. Yeah, sure. I'll take the first portion, you know, on the API synthesis and the formulation. This is actually an effort that we've had since we took the project over, as far as making the synthesis process more, instead of an extract, clearly a purely synthetic process. That's what we've developed over time since we made the acquisition, and we've optimized the process. It still needs some little work, but we are getting there. So this is not like something we're just initiating right now, clearly. So that's been work that has been ongoing. And similarly with the formulation. So, the formulation that is being tested in this study, and will be tested initially in the Phase IIb study, is also a new formulation that we developed, with the extended release. Clearly, we will be looking if there is any other avenues from a formulation point of view that will also improve tolerability. You bet we can be looking at it. Clearly, that's an area of extreme, you know, strength and competency that we have as a company. As far as use of an antiemetic and the commercial aspect of it, and then I'll let Jonathan talk about the tolerability and attenuation of AEs. I mean, even if we don't use antiemetic, as Jonathan mentioned, you know, earlier, the investigators really didn't use it diligently as we were hoping they should and would, and they didn't use it on too many subjects. So even without using, obviously, I know of a lot of products on the market that have a 40% nausea and a 40%. Is it ideal? Of course not. Now, clearly, when you get to this patient population, also a lot of these patients are taking so many other drugs, and a lot of these side effects end up being confounded, as far as all these drugs contributing. They do tend to tolerate more, you know, some of these issues and willing to stick with the drug because of their situation and condition, specifically if they are more severe patients, clearly, and specifically if they know that if they can tolerate it and get to the 3-4 milligram BID, or whatever ends up being the actual dose, you know, daily dose, and they can see somewhere in the 74-80 or even seizure freedom, they might be willing actually to do that and put up with the titration, put up with the, you know, the nausea, the vomiting, and so forth, because clearly the gold standard here is you really need to control these seizures. Unfortunately, as these seizures continue over time, progress over time, their condition worsens, and their ability, even their ability to achieve seizure freedom starts to go away over time. So even if we don't use antiemetic, what I'm saying, I guess, is there is a profile here that we see can be doable. It is, you know, we can live by it by just using more antiemetic or by just sticking to it. But we feel very good about our chances of improving, you know, the tolerability profile. And we have some, you know, couple good ideas that we think we can pursue and that we will be pursuing. Jonathan? Yeah. So in answer to your second question, we looked at adverse events over time and also by dose. We looked at overall adverse events, we looked at cholinergic adverse events, and then we looked at emetic events for either nausea or vomiting as a category. When we looked at that, and we looked at it by onset of the event, we saw that the onset of the event tends to occur early. It tends to occur within the first several weeks of titration. When we looked at it by dose, it tends to occur before getting to 2 milligrams. So the take-home from that is we believe that using an antiemetic early, in the titration phase, will be able to prevent the onset of those events and get the person over the hump where they can let their natural tolerability to the cholinergic effects emerge. This, by the way, has been seen, as I mentioned earlier, the tolerability to the cholinergic events has been seen with other acetylcholinesterase inhibitors. And so we believe using the medication early on may enable us to get to higher doses and also allow patients to stay on the drug. That's helpful. So let me just sneak in a quick follow-up just on the discontinuation. So you had 9 discontinued due an AE, 2 lack of efficacy, 2 withdrawal by subjects, so that's 13, but you had—you went from 41 to 19 patients in the maintenance phase. So were there other patients who were just lost to follow-up? Is that what's happening here? Not quite. So as I mentioned, this is an ongoing study. In terms of the breakdown, we didn't present the data in this way, but just to help you get a sense. 41 subjects were enrolled in the safety population, got at least one dose of huperzine. And, of those 41, 14 completed the maintenance, 15 discontinued, and you saw the discontinuation data. And there are 12 who are ongoing, who are still in the maintenance phase of the study. Got it. Thank you. Thank you. One moment for the next question. Our next question will be coming from Stacy Ku of TD Cowen. Your line is open. Okay, wonderful. Congrats on the data, and thanks for taking our questions. So just first, to be more specific, SK Biopharmaceuticals, Xcopri, it has had success, because it's a really good effective agent despite tolerability limitations. So can you just first talk about the clinician prescribing and practicing that you're seeing there as you think about SPN-817 and their long-term opportunity? So that's the first question, just big picture, where you think SPN-817 could go. And then for the patients that got to 3-4 milligrams, it seems like it's roughly 30%, kind of depends on how you kind of cut the data. But you talked about the antiemetics, but how else can you go to reduce discontinuation? So can you kind of go into more details around your key learnings? Is it also setting expectations as we think about the Phase IIb or even continuation of this study? And then obviously for the Phase IIb, will the longer titration schedule help? So that's kind of a two-part second question. And then just last, a bit of a clarification. Of the six patients that got the higher doses during maintenance, did they all take antiemetics? And then for the patients with improved cognition, did you, maybe I missed this, but what doses were they at to achieve improvements? Thank you so much. Okay, Stacy, well, I'm gonna try to see you. Hopefully, if we didn't, if we missed something, please let us know. As far as the long-term opportunity, starting first with the big picture, and you're right, I mean, you know, the Xcopri or other, other brand, this is not—I mean, the, in, in epilepsy, it's not unusual sometimes to have people who have to have long titration. So, that is not something that, you know, we think from a commercial potential will, you know, curtail the potential of this and how big this opportunity can be. What we believe is really important in epilepsy, efficacy is the most important thing. I mean, that's why physicians, basically, and it's an area where we know 30%-40% of patients become refractory. I mean, efficacy is extremely important in this space. A lot of patients, they are willing to titrate and titrate longer, and if they need to use an antiemetic or whatever it is, you know, they will be willing to do that because a lot of these patients, unfortunately, 33%-40% or whatever the exact number is, they end up being refractory. They end up on 3 or 4 other medications, and the gold standard goal, which is really seizure control, you know, they, they will do a lot of things to get there and to get them. And if the drug continues to have this profile, our drug continues to show this profile, and that is potentially the reward for them if they stick with the drug and they get to these doses that we're seeing right now as potentially effective doses, we think this could be a very, you know, a big product in the marketplace. Because the need out there, we all know, is big, it's huge. As many as drugs are available today on the marketplace, there is so much need out there as far as people who are treated, and yet they are not controlled. So they are very much underserved with all the current therapies on the marketplace. As far as what else can we use other than antiemetic, I don't wanna be too specific at this point, so I'll reserve that for, you know, later disclosure at the appropriate time. But we have, you know, as I mentioned, a couple other things that we're looking at, that could, you know, potentially impact the AEs and, and get us, you know, to where we really would like to be. And then as far as the implications of the Phase IIb, I mean, clearly, you know, one of the things we mentioned is the antiemetic use. We would look at the titration period. Maybe we wanna get actually patients to the 3-4 milligram quicker. I don't know. You know, we're exploring all that as we speak and as we're analyzing more and more of the data. Jonathan, anything I missed or? Well- Okay, under- For the six subjects who you were asking about getting antiemetics, no, not all of them got antiemetics. And antiemetics, for the seven subjects that it was used, it was only used sparingly. PRN, they would get one or two, just a few doses here and there, and we feel like with more aggressive and consistent early use, that patients potentially could do better. I see. Did you, what percentage of the six patients that got to the higher doses needed antiemetics? Just trying to understand if using the antiemetics is going to allow you to get to the higher doses where we're gonna see that really impressive efficacy versus, you know, the- Yeah. general lower doses? We believe so, if—and that's what Jonathan is referring to—if they use it as they should, should use it, and if they use it early enough. So although we did see some use of antiemetics, you know, in the Phase IIa, but investigators didn't use it, first of all, early enough, as soon as they should have. And if it was used, it was only used PRN instead of consistently to allow people to really tolerate these medications and get used to the cholinergic side effects. So that, that's the issue we faced in the Phase IIa, and that's why we believe, you know, it is certainly a strategy that is worth pursuing and should bear, you know, good results for us. I see. So very little kind of, let's say, correlation between getting to higher doses and the antiemetics. Yeah, I mean, we couldn't because we don't have enough data, and it was so sporadic, you know, some did use it, some used it only, like, one day out of, I don't know, 20 or whatever, I'm just making up the... I mean, it was really very random and not consistent- I see. and not early enough. Not early enough, that's the other important thing. Yeah. Okay. And then the improved cognition, the patients that achieved improved cognition, what doses were they at? If I missed, I might have missed that. Yeah, I don't have off the top of my head. We would have to get back, but I mean, we can certainly report that at a future call or in poster. Okay, understood. Yeah. Thank you so much. We don't have that here. Yeah, sure. Thank you. As a reminder, if you would like to ask a question, please press star one one on your telephone. One moment for the next question. Our next question will be coming from Annabel Samimy of Stifel. Your line is open. Hi, thanks for taking my question. I just wanted to follow up on something that you said before asking my questions. I guess in the press release, in the slides, you said the 19 completed maintenance, but when you were answering the discontinuation questions, you stated that 14 completed maintenance, 12 are ongoing, and 15 discontinued. So, is it 19 that completed maintenance? Or, I guess I'm not understanding the numbers based on what you just said. So 19, we have data in maintenance. This is an ongoing study. So, 14 have completed maintenance, and of the 19, five are still in the maintenance phase. They haven't finished it yet. Okay. Okay, I see, got it. And, I guess going back to, how you might manage this tolerability issues. It doesn't seem like the nausea and the AEs are dose-dependent. Am I understanding that incorrectly? Because it-- I mean, your ability to titrate up, it seems critical in this event, right? To get to that 3-4 milligram dose to get the efficacy. But, you know, is it actually dose dependent? Have you identified that they are dose dependent? Well, let me clarify one thing. Yes, if you go to 3-4 milligram, yes, you're going to get the 75%, it looks like from the data, the 75% reduction, 85% reduction. But across all the doses, even the low doses, we saw some pretty good efficacy, not at the 74 and 86. I just want to clarify that. So it's not like if you don't get to the 3 and 4, you'll never get any benefit at all from the drug. I just want to make sure, you know, that is clear, because as we reported in a couple areas across all doses, I mean, the responders are still in the 80% and 60% rates, very high responder rates. I'll let Jonathan, you know, talk about the level of antiemetics and the dosing and so forth. Yeah. So, I mean, this is a flexible dose study that doesn't really get at, dose dependency. But, as I mentioned earlier, when we look at adverse events over time and adverse events by dose, most of the adverse events, cholinergic adverse events, and nausea, vomiting events occurred at less than 2 milligrams. So it's not necessarily pushing the dose, it's getting over that initial hump, both in time and in dose, to allow the natural tolerability, the receptors will adjust to seeing acetylcholine, and allow patients to tolerate the drug. So, I think that with the help of antiemetics or other interventions, we can get people over the hump, and then once we get over that initial hump during the titration stage, they're more likely to be able to get to the 3-4 milligram dose range. Okay, so it's time dependent. Got it. Okay. And then I guess for the next study, I guess, how are you thinking about, you know, your inclusion criteria if you're getting the much better responses at greater than three ASMs, you're getting better responses, and patients have much higher seizure frequencies. Do you have any plans to enrich the next Phase IIb study for those patients, or just leave it as an all-comer type of trial? So, while we saw a higher response in the populations that you mentioned and that I covered, we did see a good response even when they didn't get to the high baseline seizure frequency. And so we will have the Phase IIb as all comers, because we, well, it'll be greater than or equal to 4, which is typically used. And that allows for... We don't want to restrict the use of this drug. We want to enable many patients to be able to take it. But as I mentioned, if we can get people to 3-4 milligrams, regardless of their baseline seizure frequency, regardless of the number of anti-seizure medications that they're on, we believe that they're going to do better. Okay. And then, one last question. I think you mentioned it earlier, but in terms of EpiTrack, I think you said clinically meaningful was one improvement in one point, I guess, or whatever that measurement is. Is that, is that correct? Did I hear that incorrectly, or I guess, what is clinically mean? Can you just repeat what was clinically meaningful as far as EpiTrack is concerned? Yeah. So the clinically meaningful on EpiTrack for an individual is four or higher. And EpiTrack can be analyzed in a variety of ways. So we talked about improvement, moving from one area, like significantly impaired to average. That's one way of analyzing it. You can look at the overall mean improvement. 2.3 is good. I would mention that one clinical trial reported a change of one, and it was considered statistically significant. Now, that was with a much larger sample size, but just to give you a sense, they found that the change of one in the group mean, an improvement of one, was clinically meaningful. And so again, overall, we saw that five out of 12 or 42% improved. Consistent with an acetylcholinesterase inhibitor, we believe that this drug has the potential for cognitive improvement, but we're going to have to look at that with a much larger sample size and in a placebo-controlled fashion. Okay, great. Thank you. Thank you. This does conclude the Q&A session, and I would like to turn the call back over to Jack for closing remarks. Please go ahead. Thank you all for joining us this afternoon. We are very encouraged by this interim analysis that seems to suggest that SPN-817 can be a highly differentiated product for the treatment of focal seizures. We look forward to reporting the final and full results in the second half of this year. Thank you. Thank you all for joining. This concludes today's conference call. You may disconnect.