Welcome everyone to the 41st Annual JP Morgan Health Care Conference. My name is Tessa Romero. I'm one of the Senior Biotech Analysts here at JP Morgan. I'm joined by Taylor Hanley and Atoraj Shahan from the team. We are pleased to welcome Xenon Pharmaceuticals to kick off our first day of the conference. Speaking on behalf of the company, we have CEO Ian Mortimer. Before I turn it over to Ian, I just wanted to highlight the Q&A. There will be a Q&A coming up here. There is an ask a question for those folks listening on the webcast, and I'm happy to ask the question on your behalf. With that, Ian, over to you. Thanks, Tess, good morning, everyone. Great to be here, great to kick off JPMorgan first thing on a Monday morning. Tremendous amount of progress at Xenon over the last 12 months, we'll review some of that, we'll also review the milestones going forward for the company. Presentation about 20 minutes or so, we can get into Q&A. Before I jump in, I'm joined by two of my colleagues at Xenon today. Sherry Aulin, our Chief Financial Officer, is at the front here. She'll join for Q&A. Andrea DiFabio, Chief Legal Officer, who just joined us recently in the last couple of months. I will be making some forward-looking statements, I do refer you to our SEC filings and the full risk factor disclosure. In terms of an overview for those that are newer to the Xenon story, we have deep expertise in drugging ion channels in the CNS. We've been doing this for close to 15 years. In today's presentation, I'm gonna focus on our lead program, XEN1101. Really the messages that I hope we can convey and communicate over the next 20 minutes is we've got a massively de-risked asset based on the phase IIb data that we released just over a year ago in our XTOL study. We've now initiated a broad phase III clinical trial in both focal epilepsy, and we had just announced this morning a phase III initiation in primary generalized tonic-clonic seizures. What we'll walk through in a few slides is this is a huge commercial opportunity for the program. We have, in addition to epilepsy, we've expanded into major depressive disorder, and we'll have data later this year, and I'll walk through the trial designs and some of the expectations for our MDD study. We have a comprehensive intellectual property portfolio with protection of the molecule out to 2039, 2040, absent extension of term, and we have an extremely strong balance sheet with over $750 million in cash at the end of Q3. We're guiding this into 2026, fully funds the phase III program for XEN1101. In terms of our pipeline and how it breaks down, as I mentioned today, I'm gonna spend all of the time on XEN1101, and I'm gonna walk you through some of the clinical data that we've generated to date, as well as the plans for our phase III program and our milestones going forward. In addition to 1101, we have a product called XEN496. This is in a phase III clinical trial for a rare pediatric epilepsy called KCNQ2. It's a developmental and epileptic encephalopathy. At the bottom of the slide, you'll see that we have an ongoing partnership with Neurocrine. They're running a molecule that we invented in our labs and licensed to them in 2019. This is a highly selective inhibitor of a sodium channel in the brain called Nav1.6. They have two phase II clinical trials ongoing, and we'll see some clinical data later this year from the clinical trial ongoing in focal epilepsy. Before I get into the details of 1101, I just wanted to provide a bit of context setting in terms of the epilepsy market. Epilepsy is actually much more common than I think many of us realize, 1 in 26 individuals will develop epilepsy at some point during their life. There's about 3 million Americans that have epilepsy. 60% of them have focal epilepsy. Another 30% of them have generalized seizures, and the vast majority of these patients have primary generalized tonic-clonic seizures. If we think about the 1101 phase III program, both in focal epilepsy, that's our X-TOLE2 and X-TOLE3 study, and the study we announced this morning in primary generalized called the X-ACKT study, we're obviously addressing the vast majority of the adult epilepsy market. If we think about how these patients are treated, we kind of see the commercial market and medical practice come together. A newly diagnosed patient is treated with a generic monotherapy drug. These are drugs like levetiracetam, Lamictal, levetiracetam is Keppra, Lamictal, and now we're seeing Vimpat being used. When I say there's a large commercial opportunity, if we look at a drug like Vimpat, this is the last drug to lose exclusivity, the most recent one. In their last full fiscal years of sales, they approached about $2 billion in annual sales. That's the commercial opportunity. After you go through that first generic drug, if you're not well controlled, your seizures are not well controlled, or if you have any tolerability issues, you often go to a second monotherapy as well, often still a generic drug. After those two step edits, that's where we see the branded medicines show up, and that's where we see polypharmacy show up as well. That's where 1101 has the opportunity. That's about 50% of the market. If we look at the 3 million Americans that have epilepsy and then the patients that we're treating with focal epilepsy and primary generalized, that's about 1 million patients that have an opportunity in the U.S. to be treated with a branded agent. When we look at 1101, and as I walk through the data, not only do we have compelling efficacy, but when we're looking at rational polypharmacy based on the mechanism of the drug and some of the other properties of the drug, this is where we think 1101 will do really well, and we'll communicate that through the slides in throughout the presentation. A little bit of background on 1101. I mean, we now are in a phase III program, so I won't dwell on our early stage data, but I will make a couple of comments that I think are important. One, there's a solid scientific rationale on the mechanism. We know it's a well-validated target genetically. Children that have a loss of function have a rare developmental and epileptic encephalopathy. We know it's extremely well-validated pharmacologically. There was a first generation drug called ezogabine developed by GSK. That drug was approved. It showed efficacy, but it had some liabilities that are overcome with 1101. If you look in the middle panel at the top, this is just a little bit of our preclinical data. Huge amount of preclinical data available on our website. What you'll see, and we see this both in vitro, in vivo pharmacology, and also in the clinic, 1101 is about 15-20 times more potent on target than ezogabine is. If you look at the bottom, in the middle panel, if you look at the bottom graph, we do get asked from time to time about any off target effects. This is just looking at one target. We often get questions around GABA. This is looking at the 1101 and ezogabine data on GABA. Clear to see that there's absolutely no activity of 1101 on GABA at more than 50 times the clinical concentrates of the drug. If you actually look at the free drug, it's more than 1,000 times the concentration of the drug. When we entered into clinical development based on what we knew in the mechanism and what we knew about ezogabine, we ran a pharmacodynamic study in phase I. There's not a lot of good biomarkers in neurology, but I think for this, we used a PD readout called transcranial magnetic stimulation, where we can actually measure hyperexcitability in the brain, so we can see whether we're getting drug to target. What you can see in the top right there is there's a clear PK/PD relationship. As we increase exposure of the drug, we're getting a greater dampening on the resting motor threshold or a measure of hyperexcitability in the brain. It was really this result or the totality of the data that allowed us to design a large phase II clinical trial, which we called X-TOL, and really get the dose selection correct for our phase II work. This is the X-TOL study. As I mentioned, we ran this in the last couple of years, and the data read out at the end of 2021. This was a 3-Arm study, sorry, a 4-Arm study, three active doses in placebo, 10 milligrams, 20 milligrams, and 25 milligrams. Then all patients had an opportunity to go to open label extension, and I'll show you some of the OLE data in a few slides. What was interesting when we read out the data was just how refractory the population was, much more so than we thought about going in, and much more so when we look at the literature. We look at that by three different measures. We look at baseline disease burden, so the number of seizures that these patients have coming into the study, and the patients had 13.5 seizures per month, which is significantly more than when we look at other drugs that have been tested in clinical development. These patients had failed more drugs, and they were on more drugs. If you look at the median patient in X-TOL, they had failed six drugs. They were on three drugs. This was the 9th or 10th drug that they had exposure to, and they had significant disease burden at baseline as well. That just puts the efficacy data into context. Here's the key efficacy readouts from the study. I'll use the same nomenclature throughout the presentation. On the left is MPC, and on the right is RR50. MPC is the median% change, and that's the key regulatory endpoint. That's the primary endpoint in terms of FDA approval. It's the primary endpoint for our phase III trial. It was the primary endpoint for this phase II study. On the right is the responder analysis. This is the percent of patients that had more than a 50% reduction in their seizure burden. That's the key regulatory endpoint for Europe. These things often track when you look at epilepsy drug development, which is very intuitive. What you'll see here is a clear dose response. As we increase in dose and in concentration of the drug, we see a clear dose response and significant efficacy at all doses. We were stat sig on every seizure reduction at every dose in this study. A very clean and clear readout. We see that both with the MPC on the left and the responder analysis on the right. I just mentioned at the bottom, the AE profile is exactly in line what we would expect for a very active drug in the CNS. Based on how challenging and refractory the patient population was, we did start to look at some subgroup analyses. As I mentioned, based on those three measures of baseline disease burden, the number of drugs these patients have failed, and the number of drugs that they were on, we were able to do an analysis where we could look at those subgroups of patients. What you'll see, I know there's a lot of graphs on here, but what you'll see is we've broken down the MPC for the 25 milligrams into either patients with less disease burden or more, had failed more drugs or fewer, were on more drugs or fewer. What you can see is the data gets even better when you look at a patient population that is less severe and less refractory, probably more like the population that we would see in the real world. One of the interesting things about 1101, not only a novel mechanism, the drug doesn't need to be titrated. Many CNS drugs and many epilepsy drugs are titrated very slowly due to adverse events. 1101 has a very long terminal elimination half-life. The drug doesn't need to be titrated. Based on that, there was a hypothesis that we may see early efficacy for the molecule. This is an analysis that we did on the X-TOL data looking at week 1 efficacy. On the left is the MPC, and on the right is the responder analysis. What you'll see again at every dose, 10, 20, and 25 milligrams, we were statistically significant at week one efficacy. No other anti-seizure medicine has early onset to efficacy on label. We're now putting this endpoint in a statistical hierarchy in phase III. It's in the phase III trial. If we can reproduce these results in phase III, it has an opportunity to talk with regulators to be able to get early onset to efficacy or week one efficacy on-label. As I mentioned, now that the double-blind data is complete, we've been interrogating the open-label data, and we're still looking at this. 97% of patients that finished the double-blind went to open-label extension. Just to orient you on this slide, we've kept the patients within their dose groups during the double-blind period. That's the placebo group, 10, 20, and 25. We've actually kept them in those groups just to illustrate once they moved to open-label extension, and now we're following these patients over an extended period of time. A couple of key messages from this slide. One, the patients that were in the placebo group or the 10-milligram dose, as they move to a higher dose of the drug, 20 milligrams in open label, their seizure reduction gets even better in those first couple of months in open label extension. The other thing to mention is that the patients continue to have even more benefit the longer they are on the drug. We now have this data cut out to 18 months of open label extension. This is data that we presented at the epilepsy meeting, last month in Nashville, and you can see that the population continues to do better over time. The other thing that I'll mention that's not on this slide, but we did talk about in Nashville last month, is seizure freedom. Just as a reminder, the baseline seizure burden for these patients was 13.5 per month. That's a seizure every other day. We now have approximately 20% of patients in open label extension that have gone six months with no seizure, and about 10% of patients have gone 12 months with no seizure. That's absolutely remarkable that you have a population that's having a seizure every other day to having long periods of seizure freedom. Massive increase in quality of life. These patients can now drive, they can work more, they can be back in the workforce. Based on all of this information, last year we had an end of phase II meeting with FDA. Very productive meeting. Out of that meeting, a couple of things. One, we were able to anchor the phase III program. We anchored exactly what we need at the time of NDA, and we also will file after our first phase III. That means is that we'll use that phase IIb XTOL data that I walked you through as one of the studies that we'll file on. After the first phase III clinical trial is completed, which we're calling X-TOLE2, we will file on that data package. We're now initiating two phase III clinical trials in Focal Onset Seizures, X-TOLE2 and X-TOLE3. They're identical. We have initiated X-TOLE2. That was initiated in November. We've disclosed. Very similar study to XTOL. Again, we're taking everything we learned in phase II and trying to reproduce it in the phase III clinical trial. About 360 subjects in these studies. 1-to-1 randomization, placebo, and two active doses, 15 milligrams and 25 milligrams. As I mentioned, the primary endpoint is exactly the same as we had in phase II, and many of the secondary endpoints are as well, including that week one efficacy endpoint is in the statistical hierarchy, as I mentioned. Patients also have the opportunity to go on to open-label extension after the double-blind period. As we mentioned this morning, we've now initiated a second phase III clinical trial, this time in primary generalized tonic-clonic seizures. We had this discussion with FDA as well. This is a little bit different in terms of the development path that Xenon taking versus other companies that have developed anti-seizure medicines. The more normal path is to develop a drug in focal epilepsy. That's the largest commercial opportunity, post-approval, run a study in primary generalized tonic-clonic seizures. We're doing this in parallel. We've anchored with FDA that a single study in primary generalized tonic-clonic seizures could either be part of the NDA or part of an sNDA, depending on timing. We're looking at the high dose 25 milligrams versus placebo. There's lots of good scientific rationale on why we believe 1101 should work in primary generalized tonic-clonic seizures. We can get into some of that in the Q&A. As I mentioned, we've also expanded the development of XEN1101 outside of epilepsy into depression for a couple of reasons. Obviously, major depressive disorder, massive unmet medical need. What we also know is that depression is the most common comorbidity in epilepsy. Of the lifetime comorbidity rate is up to 50% of epilepsy patients will have depression. If we can have XEN1101 with a novel mechanism, QD dosing, early onset to efficacy, and potentially having some mood benefits, clearly differentiated from almost any other anti-seizure medicine available. The reason that we're excited about MDD is there's a wide body of preclinical data, including in chronic social defeat. Also there was a very interesting paper published last year by a group at Max Planck and at the Weizmann Institute that showed that the long-term antidepressive benefits of ketamine is likely through an upregulation of Kv7.2 in the brain. We're learning more and more about the mechanism and the connection to the antidepressive effect. There's also clinical data on the mechanism in depression. Ezogabine, as I mentioned, that first generation drug was run in a phase II clinical trial with our collaborators at Mount Sinai. They're now running a similar study with 1101. The data on the right side of the slide is that they were statistically significant in clinical scales of depression as measured by MADRS, clinical scales of anhedonia as measured by SHAPS. We're doing a similar study in a similar population, just a little bit larger in terms of powering. This is the trial design, what we're calling X-NOVA. Two active doses in placebo, 1-to-1-to-1 randomization, 10 milligrams and 20 milligrams. Primary endpoint is MADRS at 6 weeks, and we'll have data. This study's gone extremely well. We initiated it last year, and we'll have data from this study in Q3 of this year. In summary, I hope what we've been able to communicate so far this morning is that we have a significantly differentiated drug, massively de-risked clinical data with our X-TOL readout. We have a drug with a novel mechanism, QD, early onset to efficacy, and it'll be an only-in-class mechanism when approved in patients that are treated with rational polypharmacy. We're expanding outside of focal epilepsy into primary generalized tonic-clonic seizures with a phase III trial initiated today, and also into major depressive disorder with data later this year. Some of the milestones coming up, we've talked a lot about the phase III program for 1101. Obviously, it's a critical year of execution. We have the X-TOLE2 study up and running and X-ACKT up and running, and our X-TOLE3 study, which is our 3rd phase III clinical trial, will be up and running in the near term. A massive amount of work in terms of executing against the phase III program. As I mentioned, we have full agreement on FDA on what we need in terms of the phase III program at time of the NDA filing. The MDD study is ongoing. It'll read out later this year. From one of our partner programs, Neurocrine, the sole inhibitor of Nav1.6, we're gonna see phase II data in focal onset seizures in the second half of this year as well. Tess, I think that's a good overview and happy to jump into Q&A. Great. Thanks Ian for the presentation here. Yeah, we'll just jump right into it. Can I just ask that someone from the presentation team take a look at the iPad because I think we've got the wrong company on here. I'll start us off here. Maybe I'll start with XEN1101 in focal onset epilepsy. You described your phase IIb data in some detail, Ian. What gives you the most confidence that the product is emerging as a differentiated treatment option in treatment-resistant focal onset seizures? Is it seizure freedom rates or any other attributes of the drug that are really resonating with physicians? Yeah, I think it's a good question. We, you know, we just came off of the epilepsy meeting, as I mentioned in Nashville, the AES meeting, where we had more than 200 folks come through our scientific exhibit. We had a massive number of one-on-one meetings with investigators. I think we're getting a lot of the feedback on 1101. Maybe a couple of comments just on the first part of your question, kind of the phase II to phase III, and then some of the differentiating features as well. I think one of the nice things about epilepsy in terms of neurology is reproducibility is really high. Drugs that work in phase II work in phase III. Drugs that work in 1 study generally work in their second or third study. I think we have high confidence going into phase III The regulatory endpoints are very clear. As I mentioned, the primary efficacy endpoint is this MPC. It's really clear on what we need to achieve. You know, I would say at the high dose in phase III, we have more than 99% power. That gives you a bit of an idea of the effect size in phase II moving into the phase III program. You know, I think a lot of what I've just discussed is how do we get the drug approved. I think your question's maybe a little bit more broad, which is what about commercial adoption? I think it's everything we've talked about so far this morning, a novel mechanism, right? If we think about just the mechanisms available, to treat these patients, the vast majority of them are sodium channel blockers. there is, you know, Keppra and Briviact or SV2A. We have some drugs that are used a little bit less frequently in focal epilepsy, that are GABA drugs. I think having a novel mechanism is completely new for physicians that they can add to that backbone of things, drugs like levetiracetam and lacosamide that are used quite frequently. Just the QD dosing, no titration, and the early onset to efficacy are all things that I think will differentiate us from other branded medicines. I think there's just a number of features that we get feedback, very positive feedback in our market research on 1101. Is the success in your phase IIIs here really reproducing the efficacy seen in XTOL on your, kind of your key efficacy measures? Are there any elements of the X-TOLE2 and X-TOLE3 designs that could alter the baseline characteristics of the patients in the under study, that we should be thinking about, for that, for those readouts? The inclusion/exclusion criteria for phase III is exactly the same as the phase II program. I mean, what I mentioned when I described going into the XTOL study, I don't think we thought that the patients were gonna be as refractory as they were based on those measures of baseline seizure burden, and as well by the number of drugs these patients have failed or the con meds that they were on coming into study. There is an opportunity that maybe the phase III population is a little bit less severe. You know, it's a hypothesis. We don't know the answer to this. XTOL was run during the early days of the pandemic, and maybe we just had a more severe population in that study. The inclusion/exclusion criteria are the same between phase II and phase III. We really don't expect much of a difference in the patient population. Okay. I just wanna make sure that everyone in the room knows that they're free to kind of wave their hand and ask a question. If not, I'll just keep going here. What are the kind of the key safety considerations for XEN1101, and how does the profile of the drug stack up against other commercial agents that are available for these patients? Yeah. It's, we've shown all of our safety data. You can go and look at the posters that we've presented at AES over the last couple of years. We have our AE tables out there. I think, a lot of disclosure on the molecule. These are all anti-seizure medicines that are reducing hyperexcitability in the brain are gonna have adverse events associated with that. These are on target adverse events, C-Max related, things like dizziness, somnolence, fatigue, and headache. Those were kind of the four highest AEs that we saw in the double-blind period. We would say they're very consistent with other, with other anti-seizure medicines that are very active. We do see a certain amount of that. None of those really, you know, patients don't, they stay on drugs. Most of the CNS related adverse events that I just mentioned usually show up earlier in dosing. As patients move to a new therapy, you see that. We've done these PK/PD models both in efficacy but also in safety. We can track where these AEs show up and how they show up, and often a lot of those CNS adverse events show up earlier in the dosing. There's a tolerability that's built up over time. I would say the AE profile of 1101 is completely consistent with what we see for very active drugs. Okay. You talked about, Ian, how the X-TOLE2 trial recently initiated. You've now got X-ACKT up and running as well. Maybe you could give us a little bit of a sense of what you think the enrollment curves might look like for these two trials and what kind of cadence of data we should expect for two, three, and then X-ACKT. Perfect. Sherry? At this point, Tess, I would say our best estimate for X-TOLE2 timing is really gonna be what we saw with XTOL. That study or phase IIb took about two and a half years from start to finish. We did run that study through COVID. In early 2020, we had actually a significant decline in our patient screening, and we don't expect to have that same impact from COVID or the pandemic this time around with our phase IIII studies. The phase III studies are a little bit larger, as Ian Mortimer mentioned, where each study is about 360 patients. Our phase IIb was 325, and the dosing period's a little bit longer. We had eight weeks of dosing in phase IIb, and now we're up to 12 weeks. Roughly we're thinking that X-TOL2 and 3 will take about 2 to 2.5 years from start to finish. X-TOL2 is really gating for us to get to NDA. As Ian mentioned, we expect to include X-TOL as part of our package, our NDA package, we're really awaiting data from X-TOL2 to file our NDA. An expected timeline at this point, based on what I mentioned, will be late data in late 2024, early 2025. Obviously once we get a bolus of sites up and running and we see what that enrollment curve looks like, then we can guide more specifically around top-line data. We don't usually give specific guidance around enrollment curves as we go through the study, but we will in the coming months refine that guidance. When we think about X-ACKT, so X-ACKT will run in parallel, as we mentioned. Our release this morning, let everybody know that we have initiated that study. That study will run in parallel. It is a smaller study. It's 160 patients. But as Ian noted through the epi data, it's less prevalent. There are less patients that have primary generalized tonic-clonic seizures. We do expect that that study will be a little bit more challenging to recruit. We will gauge whether that will be included within our NDA or potentially as an sNDA shortly thereafter, depending on when we have from that study. Maybe just to add to that. One of the benefits that we have in running a large phase IIb study like X-TOL, XTOL was run at about 80 centers. We're going back to all of those same centers to run the phase III program. You know, there'll be a lot of overlap on X-TOLE2 with the XTOL sites. We can have both the X-ACKT study and the X-TOLE2 or X-TOLE3 studies running at the same site. You can use the same investigator. If they have a patient that has focal epilepsy, they can go left into X-TOLE2 or X-TOLE3. If they have primary generalized tonic-clonic seizures, they can go right into the X-ACKT study. There's, you know, we already have investigators that have experience with the drug. They're treating patients in open label extension. We do hope not just from the pandemic, but also just experience with the drug and the compelling efficacy, the recruitment should go well in phase III. Any audience questions here? Quiet group. Okay. Curious to get your take on what portion of the 1.8 million FOS patients that are in the U.S. do you envision being potential candidates for a treatment like XEN1101 at the time of a potential approval? Are there plans to evaluate the candidate in earlier lines of therapy in focal seizures? The clinical development for these molecules is pretty standard. You know, the phase III program, as I talked about, you know, the inclusion/exclusion criteria is the same as XTOL. Essentially, these will be patients that have had their disease for quite a period of time. As I mentioned, they're reasonably to treat in a clinical population. In the real world, we will absolutely get patients that are less severe. We see that with all the drugs. We may do some phase IV work to look at other populations and those that are less heavily pretreated, but the phase III population is pretty standard. Okay. Maybe it makes sense to switch gears a little bit to kind of the pipeline and talk a little bit about depression here. Okay. You've got your X-NOVA phase II trial ongoing. Maybe it makes sense to just provide a little bit of a framework for what data we could see here in the third quarter. What are kind of the key factors that you're gonna be considering if you, if you think about moving this program forward in depression or not? Sure. Sherry, do you wanna do the top line data, and I can walk through some of the strategic options we have in depression? Absolutely. Our top line data release will be really similar to what folks have seen previously with data releases, like we did with XTOL back in the fall of 2021. We'll show, you know, key primary and secondary endpoint results. Our primary endpoint here is the MADRS endpoint at six weeks. We'll provide obviously that information as well as all the safety details. We provided pretty detailed information with XTOL, as Ian mentioned, you know, safety tables, to show the ADs that we saw with the drug. Then strategically, if we think about 1101 or Kv modulation in depression, as I mentioned, depression is a key comorbidity in epilepsy, continuing to generate data to differentiate 1101 in the epilepsy population, I think is gonna be important. We have a fair bit of flexibility here. 1101, you know, we have the opportunity to continue to do work in depression. This could be a strategy where we continue to differentiate on the epilepsy call point, obviously the first approval of the drug will be in epilepsy. The other thing that we really benefit from having been in the ion channel space for many, many years is we've got other molecules that target Kv. I think we probably have one of the broadest, if not the largest drug discovery group in ion channel research, and so we have a lot of optionalities as we think about the rest of the portfolio. Maybe just digging deeper a little bit here on the primary endpoint of the MADRS. I think that primary endpoint is taken out at six weeks. Could you elaborate for us a little bit on what is considered clinically meaningful or relevant? I think it's powered for a 4-5 point delta between the two arms. Just orient us a little bit to the, to that endpoint and kind of what docs suggest would get them excited. I mean, I think the question's gotten a little bit just about some of the challenges in running depression studies, right? You know, we often see a greater effect size sometimes in early clinical development, and those collapse as we move forward. Lots of drugs that are both in development and recently approved have been approved on a very small separation between active and placebo, only 2 points. If you go back to the slide that I showed in the presentation on ezogabine in major depressive disorder. Oh, great. If you look at the, y eah. No, the next one. Yeah. Oh, there we go. The one after this. Sorry. Before. One before this. Yeah. Perfect. Yeah. Thank you. If you look at the top, graph there on MADRS for ezogabine, if you look at their week five data, that was a 7.9-point separation. The way that we've powered, the X-NOVA study is larger. This was an N of about just over 40, about just over 20 per group. You can see the N numbers in the top right. We have 50 subjects per arm, so we have a larger sample size than this ezogabine study. We have good power at a 4-point separation between active and placebo. Looking, if you think about a 7.9 in the previous study, we're powered for about a 4, so about half the effect size that was seen with ezogabine. I think that's appropriate for a proof of concept study, for sure. And we feel confident based on this growing body of data of looking at Kv modulation, either in chronic social defeat, the new ketamine data that's come out, or this clinical data, I think, we feel really confident going into this study. I guess embedded in that, Ian, like, what are your expectations for how the placebo arm could perform here? What trial design details might have been implemented in order to help limit any placebo arm outperformance that you could see? I mean, I think you've just hit on one of the key challenges in running studies in depression, and quite frankly, some of the easier stuff in running clinical studies in epilepsy, right? You know, I think the epilepsy placebo rate can if you're going to the right sites, and the right types of patients and the right investors, I think you can manage that, and we got it right in our epilepsy drug development. Placebo rates in depression, can be more challenging. We're doing a number of the things that people would be familiar with. We're using the MassGen Savor criteria. We're at about 15-18 sites, U.S. only. We're being very careful with patient selection, and with site selection and the investigators that we're using in the study, and really trying to manage that as best we can. Just one more here from me. What gives you kind of the confidence that you've enrolled the right patients for this trial? I know it's a monotherapy study, which is pretty normal, but anything on the kind of inclusion, exclusion criteria that you'd point out? I mean, we're using inclusion, exclusion criteria where ezogabine had success. I think we're trying to be true to a clinical experiment with ezogabine that as we see on this slide, was published in 2021, and ensuring that our inclusion, exclusion criteria can be as close to that as well. Okay. Maybe, you know, last one to kind of round up our session here. You know, are there any other assets or opportunities from the Xenon platform that we should be keeping an eye on in 2023 and, you know, anything we should be watching that we haven't kind of touched on here, Ian? Yeah. I mean, I love this question because I'd love to talk about our drug discovery portfolio for ages. We spend all of our time talking about XEN1101 as the lead and most advanced program. Yeah, I think we're doing some really interesting stuff pre-clinically. Most of it has not been publicly disclosed. You'll see those molecules advance from our discovery portfolio over the next number of years. One target that I think we're especially interested in that we have shown some data publicly is on Nav1.1. We have potentiators of Nav1.1. Many of you have looked at the companies that have developed drugs for Dravet syndrome in the past. 80%-90% of patients with Dravet syndrome have a loss of function and a 50% loss of function in Nav1.1. To be able to potentiate that, there are companies that are trying to use an ASO or a gene therapy approach, but we have orally available small molecules where we can potentiate an increased current through the wild type channel, and some of that data pre-clinically is really intrig. We could be moving... You know, I think the goal in some of these developmental and epileptic encephalopathies is to move from those seizure reduction endpoints to actually having an impact on development, potentially disease modifying, and this would be a small molecule on target effect of that. I think that's that's fascinating. I should mention the Neurocrine collaboration, right? I mean, again, nobody has developed a highly selective inhibitor of Nav1.6 before. We're really excited to see the data later this year. Remember, a mainstay of treating focal epilepsy patients are these sodium channel blockers that don't have isoform subselectivity. This is the first drug that ever has had isoform subselectivity, where we only target Nav1.6, and we have these huge therapeutic indices over the other channels. The opportunity there, both in the genetic population, the children have a gain of function in the channel, but also in focal epilepsy, when we think about the success of drugs like lamotrigine or lacosamide, I think it's fascinating the work we've done in sodium channels. Great. Well, I think we're out of time here. I thank you so much for the presentation and for everyone for joining us today and I hope everyone has a great rest of the conference. Thanks, Tess. Thank you. Thanks.