Ladies and gentlemen, the program is about to begin. At this time, it is my pleasure to turn the program over to Jason. Thank you, operator, and good day, everybody. Thanks so much for joining us for the BofA Annual CNS Day event. I'm pleased to be introducing Xenon Pharmaceuticals and CEO, Ian Mortimer, and Chief Commercial Officer, Chris von Seggern. So, gentlemen, thank you so much for joining us today. I think, Ian, you had a few opening remarks, and then, from there, we'll jump into Q&A. Yeah, happy to. Thanks very much, Jason. Thanks to you and the BofA team for hosting us today. I think a really important time, actually. This has been a big year of execution for Xenon, so really nice to kind of check in on how we're doing. And I'm really pleased to be joined with Chris von Seggern today, our Chief Commercial Officer, as you mentioned. I know a number of the questions will be around really just where we see the lead asset fit in commercially both in epilepsy and in major depressive disorder. So it's really nice to have Chris here and provide a lot of the work that Chris and the team have been doing in preparing the market. For many people who know us well, you know, obviously, we're a neurology company, really deep expertise in drugging ion channels in the CNS. We really have people focus on three key areas in the business. One is the lead molecule, azetukalner, in epilepsy. The second is azetukalner as we broaden into psychiatry, and we'll talk about that today. Then third, we're starting to talk a little bit more about the maturing discovery pipeline at Xenon, and there's three targets that we like a lot. We're doing even more work behind those three targets, but there's three targets that we've been spending a lot of time on, and you're going to see multiple molecules transition into human clinical development from our discovery portfolio over the next year or two. So hopefully, we can spend some time there as well. But for many that know us well, really think about azetukalner at least first in epilepsy. And really, our broad investment in epilepsy, we're running three phase 3 clinical trials in parallel, two in focal onset seizures and one in primary generalized tonic-clonic seizures. And our real commitment and broad investment here is based on some extremely compelling phase 2 data from a study called the X-TOLL study that we disclosed publicly a couple of years ago, at least the double-blind data. And then we've been following these patients for multiple years in open-label extension. And actually, we're going to have some data from OLE, some more mature data at the American Epilepsy Society meeting in Los Angeles in December, just around the corner. We now have our first patients at five plus years of dosing, over 600 patient years of exposure. So we have a huge amount of data on the long-term efficacy and safety of the molecule. But I know we'll get in today, but we really think the profile of azetukalner is very compelling in epilepsy based on the phase 2 data from X-TOLL. You know, obviously it's an only-in-class mechanism. None of the drugs currently available target potassium channel modulation. On a placebo-adjusted basis, this is the best efficacy in the double blind ever seen in focal onset seizures in the most refractory or severe population ever trialed. So it gives us confidence just on the efficacy profile of the drug. We're also seeing that now in open label extension, where we're getting even greater seizure reduction as patients stay on the molecule longer, and we're getting these longer periods of seizure freedom. So for patients that have been on the drug at least two years, it's almost about one in four of them that are getting at least 12 months of seizure freedom, which is actually remarkable when you look at the baseline characteristics of the patients coming in, including 13 and a half seizures at baseline per month, or a seizure approximately every other day. So with an only-in-class mechanism, really significant efficacy. We have early onset to efficacy, so we see statistical significance at week 1 in the X-TOLL study. The drug doesn't need to be titrated, so that's a clear differentiator, so it has real ease of administration with no DDIs that have been identified, or we have to make any modifications to other drugs, and we're also seeing this emerging mood benefit as well, so I think, you know, when we look at the overall profile, extremely compelling in epilepsy, and we'll go a little deeper in all of those, throughout the next forty-five minutes or so. The first phase 3 trial in epilepsy, called X-TOLL 2, we expect that to read out second half of next year. That's on the critical path to filing an NDA and transitioning this molecule to being a commercial medicine. Obviously, I mentioned the mood benefit. That's a nice segue into kind of that second tier or pillar of the organization, which is really moving azetukalner into psychiatry. We read out at the end of last year a phase 2 clinical trial called the X-NOVA study, and that basis of that study, and we can get into more details, is the basis of us running three phase 3 clinical trials in major depressive disorder, and the first one of those phase 3 clinical trials is going to start in Q4 of this year, so in the near term. When we look at the profile in depression, obviously, we're seeing an important separation on clinical scales of depression, whether you look at MADRS or HAM-D17. But we think there's also other important differentiators of the molecule. One, early onset to efficacy. So, similar to what we saw in epilepsy, we're seeing in depression as well, where we get a separation early on at week one. We also know that a number of these patients have a significant comorbidity of anhedonia, and we saw statistical significance on that endpoint in our phase 2 program. Obviously, a different mechanism from how MDD is treated today and a different adverse event profile. So we're not seeing the sexual dysfunction or the weight gain that is seen with other classes of drugs that are used to treat major depressive disorder. So I think we're really interested in moving azetukalner into psychiatry and into major depressive disorder. There's also this common link where there's a significant comorbidity of depression in the epilepsy patients, and so we can talk about that as we move through the Q&A. The last thing that I had mentioned at the beginning was really our focus on the discovery platform and the maturity of that. We're focused on three different targets. Continued prosecution of Kv7. These would be additional molecules following behind azetukalner. We're also very interested in Nav.1.1 and Nav1.7 for seizure disorders and for pain respectively, and we can go into some of those details. Balance sheet's good, cash into 2027 to fully fund the late-stage clinical programs for azetukalner in both epilepsy and in depression, and a number of these molecules transitioning from discovery into human clinical development. I think it sets up the company. I know this year's been a big year for us in terms of execution, and really looking forward to twenty twenty-five and beyond in terms of a lot of clinical data going to come from Xenon and as we transition and forward integrate also into a commercial organization. Okay, great. So maybe we'll start with epilepsy and with putting, you know, your clinical data aside for a moment, just kind of curious, if you were asked the question like, what do you think makes focal onset, right, like, a good market in terms of launching a new drug, given you've got a number of generic alternatives available for you? And so that's always going to beg the question, is this a space that's going to reward innovation? So maybe I'll start there, and then I've got some follow-ups. Yeah, for sure. Yeah, we think absolutely the focal onset seizure space, although, as you mentioned, there are a number of generic drugs available. I think there's absolutely a need for innovation. And the drugs that have innovated have done really well. And so I... Chris can walk us through some of the epidemiology data, and just so we get a bit of an understanding of how big the market and what the medical need is. And then I think we should go into the attributes of the azetukalner, and really where those would fit and why we believe this could really be a real significant commercial opportunity for Xenon. Chris? Yeah, absolutely. Thanks, Ian. So when you think about the epilepsy space, it's important to note the total size of the opportunity. There are about three million adult patients in the U.S. who suffer from epilepsy, and it's split into two major forms. So the first would be focal onset seizures, which represents about 60% of the market. About 30% of the market would be primary generalized tonic-clonic seizures, the other major component of epilepsy. And a portion of patients remain with an ambiguous diagnosis that sit between those two groups. So three million adult patients, about half of them are underserved with existing therapeutics today. And despite the fact that there are a number of products that have been on the market for quite some time, you can think about with the selection of over two dozen approved products, you still cannot get meaningful seizure reduction for a very large percentage of the patient population, and that underpins the unmet medical need here. Part of the challenge is many of the therapeutic alternatives that exist today sit within a small number of mechanistic categories. Mm-hmm. ... and there isn't mechanistic differentiation. And you can't therefore stack up medicines on top of each other because you're not going to see additional therapeutic benefit within that category. So yes, there are many products that are available, but I, it's important to appreciate that there are still many, many patients that are suffering from seizures and are not seeing an adequate response. And when we transition then to azetukalner's profile, there are a number of attributes that really are important to consider. First is that mechanistic differentiation. We're the only product with clinical data in the Kv7 space. And importantly, Kv7 is an important complement to the mainstay of treatment, which are categorically sodium channel agents- Mm-hmm ... in this space. So that mechanistic differentiation is an important, is an important attribute. But there are many other attributes that are important with a profile like azetukalner. Rapidity of onset. In the environments that we're thinking about, getting to efficacy quickly is an important consideration for these patients. Most of the other products require titration, so that's a complement to the rapidity of onset. If you have a product that requires titration over the course of weeks or months, you're living with that risk of an unprovoked seizure happening during that period of time. Ian has mentioned the comment around DDIs. Given that much of this market is combination treatment for patients who are difficult to treat, you can imagine the importance of a medicine that can play well with others. Mm-hmm. Really, the last piece of the equation, which is new to the story with azetukalner, is the potential to address mood. Mood is a very significant comorbidity within the epilepsy space. We can spend more time on that in a moment. Okay. How- Jason, maybe just to add to that, I mean, I think we can look at some other commercial proxies here, right? Why have certain drugs done really well in the category? The three that really come to mind are Keppra, Lamictal, and Vimpat, right? All blockbuster drugs and all had clear differentiating features, right? Keppra was a novel mechanism at the time. The data were really strong. Lamictal, although it was a sodium channel inhibitor, really had this mood-stabilizing benefit or differentiating factor. Vimpat is really widely recognized as a drug that's quite easy to use and easy to administer and to provide in combination with other therapies. So each of those had different differentiating factors that led to a large commercial opportunity. And then if we look at azetukalner, I actually think the list of differentiating features and compelling properties of azetukalner is even longer, right? We have the novel mechanism, we have the compelling efficacy, the early onset to efficacy, and now what we're seeing is this emerging profile in mood as well. Mm-hmm. I actually think there's a real unique opportunity for azetukalner in the FOS space. How would you... Ah, a lot of people focus on the XCOPRI relaunch and as a learning more than anything, right? You know, I think they're what? In year three or four. I believe that they launched during COVID. So there's all sorts of, I guess, caveats here, but as you look at that as a proxy, right? For, you know, does the market, you know, where new or innovative things... The things that I typically hear about XCOPRI is good on efficacy, good on, you know, driving seizure freedom, not the easiest drug to onboard for patients. And so I guess I'd love to get your perspective on that as sort of like a proxy or something that you learn from as you think about go to market. Yeah. Yeah, absolutely. So first, let's put you in the mindset of a patient that's looking for an alternative therapy. So this is not a market where newly diagnosed- Mm-hmm ... patients are seeking branded therapies. As we've already discussed, there are a number of generic, generically available medicines, some of which are mainstays in treatment, levetiracetam or lamotrigine are products that are used very frequently early in lines of therapy. What's causing a patient to seek a second or a third or a you know or more line of therapy is either a tolerability issue with their existing therapeutic or a breakthrough seizure. So in many respects, you have to think about the addressable patient population for branded agents being for those patients who have an inadequate response to early line of treatment, and then you're waiting for these events to emerge, and it's the attributes of the profile that's sitting in front of you that the physician is thinking about when they're selecting for a new drug. So that's the patient population. Now, let's turn to XCOPRI. You're right, XCOPRI. I think it has some things going for it and has some challenges. They launched in the middle of COVID, and access to physicians for a new company with a new product was challenging. And from a launch perspective, they've actually done a reasonable job positioning themselves in the marketplace. They do have compelling efficacy data and seizure freedom data, and that's the... those are the main drivers for that product. But there are some limitations to XCOPRI that have really hindered use in clinical and commercial practice. The first of which is the exceptionally long titration period, and that titration period is tied to a very severe but rare adverse event called DRESS that is life-threatening. And if one accelerates the titration period for a product like XCOPRI, you could actually put the patient at risk. So what we've seen in our market research is that clinicians are holding that product for really late line patients. It's a product that's held right before one would turn to a surgical option, and it's this ease of use challenge with XCOPRI that's really held it back, in our opinion. When you turn from XCOPRI to azetukalner, that's one of the real attributes or benefits that our product has or has the potential, which is we play well with others, we have a rapidity of onset, there's no titration required. And these ease of use attributes really do play an important role earlier in lines of clinical treatment decision making. And the best analog to think of from that standpoint is Vimpat. When Vimpat was introduced into the marketplace, clinicians latched on to its ease of use attributes, and that was one of the reasons why Vimpat was often considered this first branded product. And when we conduct our market research, we often hear that the total package of azetukalner puts them in line of thinking about using the product earlier. The major difference we hear is the potential mood benefit coming does catapult the product into a different category when you think about the patient population that has unmet medical need associated with mood-related symptoms. Yeah, so I think- Yeah, Jim. There you go. I think XCOPRI, you know, as Chris has gone through, is an interesting proxy because it's the most recent branded drug that's been launched in the space, so we absolutely should be keeping an eye on it. Actually, interesting, when we launch, we will be the only two branded drugs, right? So, I think it's important to track how they've done, and I think Chris has put into perspective the strengths of that molecule and maybe some of the challenges and where azetukalner could fit in. To bring that forward to when we launch, you know, our part of our real messaging around azetukalner is gonna be that this should be the first branded drug that physicians reach for, for all of the attributes that Chris has gone through. I think XCOPRI is gonna continue to play a role, absolutely, but I think if the profile of azetukalner that we've seen so far, both in all of the clinical studies and the open-label extension, if that continues, we really expect that azetukalner will be the first branded drug used, so it's really an order also as we think about from a launch perspective. Yeah, I mean, you know, I know that over the years you've talked about, you know, based on the profile you've seen in X-TOLL, the potential to be kind of first brand, right? And that's third line, maybe mainly, but there's also some second line utilization for a first brand. But then I think more recently, you've talked about the mood benefit possibly being a swing factor that could facilitate even more early line use. So, how does that... I guess you, as long as you have a positive pivotal trial, you feel like there's a knock-on effect that could drive earlier line. I assume that's defined by second line, or just broader use with physicians knowing they want to have that adequate coverage against mood, given the high level of comorbidity? Yeah. So I think there's a lot of excellent questions kind of embedded there, right? So let's talk a little bit about the patient population, and then why they would potentially reach for a drug that could have positive mood benefit or mood stabilization benefit, and then Chris can go into some of the market research and what we're hearing, because I think the psychiatric comorbidities in epilepsy as an overall statement are. There's an underappreciation for that, and I think there's an opportunity for us to play an important educational role in the epilepsy community as well, but there's two really key things to think about in the epilepsy community. There's both, in terms of the patients having the comorbidity, and I think, at least to me, that's really intuitive, right? These patients are having breakthrough seizures. Those seizures are having an impact on their quality of life, and that's having an impact on psychiatric comorbidity, such as depression and anxiety. So I think that's part of it. The other thing is that some of the anti-seizure medicines that are used are mood negative, right? So the adverse event profile is that there is, negative mood symptoms associated with those molecules. We see that at times with levetiracetam, you see it with drugs like perampanel. And so there's both the adverse event or the exacerbation of an underlying mood condition, there's the comorbidity as well. So with azetukalner, the data that we've shown, not from the X-TOLL study, but in the X-NOVA study, and there's lots of mechanistic rationale to back this up as well, is that we are seeing an antidepressant effect of the molecule, and we think that's going to be important in the epilepsy community. But there's a huge amount of education that's going to be required as well. Chris? Yeah, absolutely. And as Ian's mentioned, we've spent a fair amount of time with our physician community, trying to explore the understanding of mood-related conditions within the epilepsy population, both from the physician perspective, but also layering in the patient perspective as well. And when we have a conversation with physicians about this, what became instantly clear to us is the lack of appreciation, the underappreciation of the importance of this comorbidity as it means, as it pertains to overall patient management. So physicians are quick to point to a product like lamotrigine as a product that they would preferentially choose for a patient with a pre-existing mood condition or one that develops over time based on the exacerbation, to Ian's point, of another anti-seizure medication. And the data that are relied on for that are coming from the bipolar data associated with lamotrigine. So it's not specific data within the epilepsy population that they're pointing to. It's just that the molecule is well understood to provide mood-related benefit. When we talk to physicians, though, there is this disconnect between their perception of mood and depression within the epilepsy population and the patient perception. Patients often report depression and depressive-related symptoms at a much higher rate than physicians do. And it's that intersection that we believe is quite important for us to address during the time as we prepare for launch. You'll see more and more from us as we think about our disease state education and how we want to connect with the community to try and close that gap, because we believe that there's a real opportunity here to improve overall patient care by addressing the comorbidities that are related beyond just the symptoms themselves. Okay. And then, you know, thinking about, you know, if, if you're able to directionally, you know, see consistent results with X-TOLL 2, when we think about sort of the ultimate regulatory review in product labeling considerations, where do you stand on whether you think retinal exams at either treatment initiation or posttreatment would be potentially required, based on any kind of like, a predecessor molecule, even if you run your trials and you have this long-term follow-up, and you don't see anything, I guess, is there a theoretical concern? How do you think about that, or would frame that for investors? Sure. Yeah, probably helpful to maybe provide just a little bit of background. You kind of, it was embedded in your question, but just so everyone has that context. So prior to azetukalner, there was a previous drug that was developed and approved in epilepsy. It's no longer commercially available. That drug was called ezogabine, in the U.S., that was the generic name. And ezogabine, what you're referring to is there was some pigmentation associated with that, with that drug. It was it showed up on cumulative dosing, so the probability in a patient increased over extended exposure to the molecule, and it showed up as pigmentation in the skin, kind of this blue-gray discoloration color, also in the lips, the gums, the nail bed, but also in the retina, and that was kind of central to your question. And so we've learned a lot from the work that GSK did. You know, we're very comfortable with the statement that this is not a class effect and this isn't mechanism-based toxicity. It was really something unfortunate in the chemistries of ezogabine and the chemistries and what happened under oxidative conditions. That drug dimerized and it was that new dimer complex, that chemical complex, that had color associated with it. So we haven't seen that with... If we just look at the chemistry of azetukalner, which is different than ezogabine, we have not seen that preclinically. We cannot, you know, we can't recapitulate what happened with ezogabine, with azetukalner. But yes, and then the question is, let's answer it clinically, because you know, because of the details with the, with ezogabine, it was on extended exposure of the molecule, and so as I mentioned, we do ophthalmology, and we are following these patients closely. We now have patients out over five years of dosing. So although I think the mechanistic argument and the chemistry argument is really solid, that we shouldn't see this with azetukalner, we need to prove it out clinically, and to prove it out clinically, you need longer term exposure. We've seen that. We now have patients, as I mentioned, out five years of dosing, and we haven't seen the pigmentation that was what they saw with ezogabine. Yeah. Ultimately with everything, all of the data is gonna be part of a review package with FDA, but both in terms of the scientific arguments as well as the clinical data that we already have with azetukalner and will continue to collect in phase 3. We're gonna have a huge amount of information to answer the question around risk of pigmentation. We haven't seen anything. We don't expect to see anything based on the underlying mechanism and Science, but we'll continue to monitor it, and that'll be a discussion with FDA. But based on our expectation today, we wouldn't see anything that would be, you know, an ex... You know, something that would be required either at treatment initiation or through treatment. Yep. Okay. And then, in terms of just, trial, enrollment, execution, things like that, you- Yeah ... there are competitors running late stage trials as well. It doesn't appear that you have a high degree of trial site overlap, and so I imagine since you met with investors in early September, not a lot has changed and that you're accruing patients in a similar timeframe. Your timelines for top line haven't changed, but just anything worth acknowledging or commenting on there? Sure. Yeah, I think sometimes a little bit of detail here is helpful. And I think we also have to remember in these studies, even when you have your last patient screened, you can be six to eight months from top line data. Although the endpoint is a twelve-week double blind period, you need these patients to go through an eight-week baseline because you need the patient to count the number of seizures they have at baseline prior to randomization to do the statistical analysis for these studies. So I think some people, you know, "Why, why can't these go faster?" There are certain steps that you just need to go through to run these studies. The other thing that I think is important to mention is, you know, our phase 3, both X-TOLL 2 and X-TOLL 3, they're identical studies, 360 subjects, randomized across three different arms, two different doses of the active drug, 15 and 25 milligrams and placebo. We go to about 100 medical centers to randomize that number of patients. So you're getting a handful of patients per medical center, and so you're gonna see some natural ebb and flow. But we are the sponsor that have run the most recent large study in this space, in X-TOLL, and we are the most advanced in running the phase 3 program in terms of X-TOLL 2 and X-TOLL 3. So I think, you know, our level of experience really shows through here. For X-TOLL 2, we've gone to a lot of the same sites as we used with X-TOLL. The benefit there, when I spend time with our investigators in one-on-one meetings and in medical congresses, many of them continue to have patients on therapy, right? So they, because they were on X-TOLL, they still have patients in open label extension from the X-TOLL program. So they have, they have these patients that are doing remarkably well. That's great for them to talk to new patients about, so I think we're clearly differentiated there. Yes, I would... You're absolutely right. There is more clinical trials ongoing today in focal onset seizures than maybe there has been at other points in time. I will say we are the only drug with the efficacy, both in a double blind period and an open label extension, and the safety that we have for the molecule. What we hear back from physicians time and time again is that they want to focus their patients, you know, on a clinical study where they really think their patients can have benefit. Sometimes you do get overlapping sites. Most of the sites run one trial at a time, and we're really focused on these key centers that have had success with us in the past in the X-TOLL 2 program because they have worked with us on X-TOLL. I think we have a significant competitive advantage here, and I know we'll finish the phase three program well in advance of the other companies. Okay. Maybe shifting gears to MDD. I was speaking to, I guess, a CEO from another company this morning who said: "Well, if I was starting a CNS business, I may not start with psychiatry, because of some of just the known challenges, right?" It was more from a commercial standpoint, right? Like the cost, the gross, the nets, all those dynamics, the number of competitive alternatives. So as you look at this space, why do you feel like it's attractive for, you know, a novel MOA? I know there's a lot of excitement also for kappa opioids, so there are- Mm-hmm ... new approaches and people are investing and seeing success with late line options. Yeah, I'm happy to start here, and Chris has done a huge amount of work here, so he can go into a lot more detail. I mean, at the highest level, there's still a significant unmet medical need here, right? And we actually, not dissimilar from epilepsy, we haven't seen enough innovation in psychiatry and enough innovation in major depressive disorder. So, I think we're proud to be part of a number of companies that are trying to bring novel mechanisms to the space, because there are just so many patients that need alternatives to current therapy. Where we think azetukalner could fit in, obviously, the novel mechanism we've talked about, the early onset to efficacy. I think what's really reassuring about the profile is we see similar adverse events, both in major depressive disorder as well as in epilepsy. We see early onset to efficacy in both therapeutic indications, and so when we look at some of the other classes in MDD, same as epilepsy. In epilepsy, it's due to titration, often. In the MDD space, often it just takes time for some of those drugs to work, so having early onset to efficacy, I think, is really good. We've also focused, as have some others, on a comorbidity within the depression space called anhedonia. And I think this, even for those patients that are getting, you know, that other therapies are helping them in the underlying mood, they're still struggling- Mm-hmm with anhedonia, and so the opportunity to help those patients, I think, is significant. And then just the AE profile, and maybe we can go, you know, you may have some more specific questions just on the AE profile in depression versus epilepsy. But the AE profile is different than what you see with the currently available drugs in MDD, so we're not seeing the sexual dysfunction or the weight gain. It's a different adverse event profile. So as Chris will go into, we've really looked at all of those characteristics in doing our market research and where could this fit in. In, as you say, there's a number of companies in the space, and novel mechanisms, which I think is really good for patients. Yeah, and building on Ian's point, when I think about the MDD space, there's a similar dynamic as what we see in epilepsy. There are mainstays of treatment here, and the SSRIs, SNRIs are categorical leaders in this space from treatment standpoint. And when you look at those products, which virtually all patients will be exposed to early in their disease course, there are real challenges with them, and the first is that they have virtually no effect on the important comorbidity of anhedonia. So they address the other components of depression, but they leave a gap in an unmet medical need from an efficacy standpoint. When you talk to clinicians, when you think about discontinuation of first or second or even third line use in of those medicines, what physicians often point to is either substantial weight gain associated with them or significant sexual dysfunction or sexual side effects that emerge. The most recent products that have come into this space, in particular, the atypicals that are now more commonly used within the depression arena, they themselves have the liability of weight gain. So we're not addressing some of the important unmet medical needs that exist in this space. And clinicians, when exposed to the profile or the likely profile of azetukalner that could emerge, we hear real strong interest in the mechanistic diversity, the ability to address anhedonia, rapidity of onset, which is a real challenge. Mm-hmm. SSRIs can take weeks to months to onboard, and then the pull can often be the AE profile to say, "Okay, well, a patient has become available for another therapeutic because they were dissatisfied with weight gain or sexual dysfunction," and that puts the azetukalner profile into the mix, for treatment selection. So when I talk to psychiatrists, what never comes up is comparison of these different drugs on their efficacy effect size deltas. Yeah. It just doesn't strike me as, like, the most data driven on the efficacy side. It almost feels like: Just give me something that's that big. If it's a novel mechanism, that certainly helps. A lot of sensitivity around tolerability, in the MDD space, and so that's my preamble to the question, right? Which is that you decided to advance the twenty milligram dose, probably a little higher than we initially thought you might go with when you were still in phase two, and so I guess just, like, your comfort level that what we saw in phase two was representative of of this dose, and maybe, you know, look, your epilepsy data you generated with twenty mg is confounded by the fact that it's basically there's a lot of other background meds. Yeah. So it's hard to tease out. And then you have the bedtime dosing, which presumably mitigates some of the Cmax-related adverse events. And so maybe that's the answer, but wanted to kind of leave it to you to maybe frame that. Sure, happy to, and then Chris can provide his perspective on the market research on the efficacy side as well, 'cause I think your comment, you know, I think is something that we hear. You're hearing from psychiatrists we hear in the work that we do as well. But yeah, you know, anytime we choose a dose for late-stage clinical development, we're gonna be informed with the information we have, and it's always gonna be that trade-off between really the therapeutic index, right, where we're seeing efficacy and what the profile is. I would say going into the X-NOVA study, you know, we used 10 and 20 milligrams in that study, and that, in those patients with moderate to severe major depressive disorder. And we saw a clear dose response, and we saw a separation on efficacy. And then when we look at the adverse event profile, I think a couple of things. One, very reassuring that there were no new adverse events. So now that we have the type of long-term exposure we have in epilepsy patients, we're not seeing new or different adverse events in MDD patients, so it's the same thing. What I think was actually you know caught us off guard to the upside, and I actually think you know in terms of Wall Street as well is actually the adverse event profile at 20 milligrams in depression looks more benign than it does in epilepsy. Again, all the caveats, these are different indications. These are cross-trial comparisons. We can never probably completely tease this apart, but I think you made an important point. In depression, in the phase 2 study and in phase 3, we're using azetukalner in a monotherapy setting. In epilepsy, these patients are on background medications. Actually, just over 50% of the patients in X-TOLL were on three other anti-seizure medicines, so this was the fourth being added. Somewhat difficult to tease apart. Yes, we have a placebo arm, so we can look at it a little bit, but somewhat challenging to tease apart because there are so many epilepsy drugs available, that the number of combinations that patients are on is significant. So to tease apart exactly how those adverse events are together when you have those background medications. But it looks like in depression, 20 milligrams is extremely well-tolerated. We are seeing some of, as you say, Cmax-related adverse events. We think that's important in terms of what we just see from a target engagement point of view. What we know in epilepsy, because we've done a lot of work here, for those CNS, those Cmax-related CNS adverse events, things like dizziness, which is the most common adverse event that we see across different populations, usually is in a dose-dependent manner, exposure-related manner, shows up early and is transient. So patients can kind of, you know, get used to it over time, or that tolerability can build up. What we'll try to do in epilepsy and in depression, you know, we'll have the opportunity to have those discussions with regulators as well, is the ability to have multiple doses on label, right? So we know not any one specific dose is going to be the right dose for any, for all patients, both on the efficacy and on the tolerability side. But, in depression, the 20 milligram dose, I think, is this real sweet spot dose in terms of the efficacy we saw, but also the adverse event profile, which as I said, is reasonably benign and lower than we expected going into the unblinding of the X-NOVA results. Yep. Okay, and maybe shifting gears to the early-stage pipeline, sodium channel, NaV1.7. And I know that the idea would be to perhaps file an IND sometime in twenty twenty-five. That's right. And so candidate selection is sort of where you're at, if I'm gathering sort of the breadcrumbs correctly. So this mechanism, NaV1.7, specifically, has had some attrition out there historically. Yeah. Selectivity and has been sort of a goal, even though I guess with Pfizer's sulfoni- what is it? Sulfonamide. Not sulfonamide, I can't pronounce it correctly, but- Sulfonamide, yeah. Yeah. That's right. Had run into some issues. I guess just how you're thinking about differentiating from those other approaches, be it either binding site or other properties that you feel like can really optimize this target. Yeah, and I'll... I'm not going to go into all of the, very detailed properties of our molecule, because I think some of that is really important to keep proprietary. But we can absolutely talk about the field, some of the challenges and where, I think we're going to do things a little bit differently. I mean, NaV1.7, for now, going on about two decades, has been a target that many companies wanted to try to prosecute against, right? And I think many know we have probably more history in this field than maybe any other company out there. We were the first to actually clone the gene many years ago, and we had a number of different approaches to drugging NaV1.7. We had partnerships in the area, a very long and an important collaboration with Genentech and Roche as well. So yeah, there's been a number of challenges with NaV1.7. The genetics are absolutely exquisite, right? So if there's homozygous loss of function, those patients feel no pain, regardless of noxious stimuli. We also have these gain-of-function phenotype as well, where if you have a gain-of-function in the channel, you feel too much pain. Mm-hmm. That's often spontaneous and non-precipitated. I think it's one of the most uniquely validated targets from a human genetics point of view. But it's been a challenging target to drug. You've touched upon some of it. Selectivity matters for sure. Not only were we the first to clone the gene, we are the first to publish the crystal structure of the protein in Science with Genentech a number of years ago. Selectivity, potency and selectivity absolutely matters. There have been tox issues with very specific chemistries of other companies. Some of these have been chemistry-related issues, some of them have been target-related issues. Receptor occupancy matters. Obviously, the human phenotype is a complete knockout. We think based on some of the more recent literature, we probably don't need to get close to 100% receptor occupancy, but you need to get higher receptor occupancy than we do, for instance, in our epilepsy targets. So it is something that you do need to hit harder than some of the other CNS targets. Biodistribution and the pharmaceutical properties of the chemistries and the molecules, we think matter a lot as well. There's a whole bunch of different things that we have learned from the work that we've done and that we've learned from the field, and we've made all of those adjustments, and some of the chemistries that we have now preclinically have really quite incredible therapeutic indices and have properties that we're really excited to test the human experiment. The other piece of information that I think is newer is that selective sodium channel inhibition can provide this analgesic effect, and that's what we're seeing with the Vertex NaV1.8 molecule. So I think the just how the field has evolved in selective sodium channel inhibition, then the specifics about learning about NaV1.7 and some of the challenges and how we've addressed those, I think we're uniquely positioned to run the human experiment. Nice thing is we know about pain is once we get through our healthy volunteer studies, you can actually get proof of concept reasonably quick because the bunionectomy studies are easy and fast to run. Is the in-house view that, you know, when it comes to the topic of, you know, does it make sense to combine NaV1.7, NaV1.8 approaches, that perhaps we don't need to do that? I'm curious, you know, we'll follow the developments in that space, but at the moment, our base case is that we may not need to combine the two approaches. Yeah, although, I'm of the perspective that at some point, the question that you have asked will be answered clinically, that someone will combine a NaV1.7 inhibitor and a NaV1.8 inhibitor in a human clinical study. That is not likely to be... Those will be two molecules, not the same chemistry that hits both targets. Mm. But look, in almost every therapeutic area that we work in, right, we've just had this long conversation around epilepsy and trying to combine drugs of different mechanisms and different targets. So, yeah, I don't think this is gonna be any different. I think combination therapy, you know, for certain types of patients, may be the way that it'll go, and I think at some point that experiment will likely be run. Whether it's necessary or not, I think it's just too early to tell. I think we're still kind of in the early innings. We need to have some human clinical data on NaV1.7. You know, obviously, the NaV1.8 program will continue to advance as well at Vertex, and NaV1.8 is a highly competitive target. There's a number of other companies in that space as well. Actually, there's probably fewer companies on NaV1.7 right now. But I would expect at some point that that experiment will be run of a combination drug. Not that it's necessary, you know, the human genetics teaches us for NaV1.7, it may not be necessary, but I expect that it'll probably be run at some point. Okay. Well, we're up against time here, but I really appreciate, you know, both of you guys spending a little time with us and sharing your perspectives on some of the latest developments at Xenon. And so with that, we can wrap up the call. That sounds great. Thanks so much, Jason. We appreciate it. All right, thanks-