At RBC Capital Markets. Really pleased to have our next presenting company, Xenon Pharmaceuticals, represented by their President and CEO, Ian Mortimer. Ian, thanks so much for being here and joining us. Yeah, thanks for having me. It's always great to be at the RBC Conference. Appreciate it. Great. Maybe we can kind of jump right in and talk about the sort of counterpivotals in epilepsy. Can we maybe start with the latest on the conduct of the X-TOLE2 and 3, phase III studies, I guess how you're feeling about the overall trial operationally? I know you mentioned on your recent earnings call some metrics that give you high confidence that you're enrolling a population that should respond similarly to what you saw in the X-TOLE phase II study. Can you talk a little bit about maybe the conduct, the types of patients that you're seeing, and kind of how you're feeling about just the ongoing studies overall? Yeah, happy to. Maybe even before I get into some of the details on the question, I'll just take a little bit of a step back. I won't give an overall corporate overview because I know we'll go into lots of parts of the business over the next 25 minutes. Specifically for azetukalner and our excitement, obviously our excitement is really to bring a novel mechanism forward in epilepsy. There are no potassium channel modulators that are available to help and treat these patients. We know still about 50% of these patients are having breakthrough seizures, and there's a need for new medicines. If we look at our phase II data, which you're referring to, because I think it's really important to put that into context, the phase II data that we had for azetukalner were incredibly robust and very, very strong, right? On a placebo-adjusted basis, this is the best efficacy ever seen, at least based on our review of the literature in focal onset seizures, really in a population that was the most refractory or challenging to treat. We have all these other attributes of the drug, from the novel mechanism to the no titration. We see early onset of activity, and we potentially also have this benefit in mood. I think just the overall profile of azetukalner and cenobamate is really interesting. That is what we hear from docs as well. Yeah. Yeah. No, it's been really consistent and good feedback from the medical community. Now if we kind of get into your question on the phase III, if we go back a couple of years ago post the phase IIb X-TOLE study where the result was really good, the X-TOLE study was about the same size as the phase III study. One of the mantras coming out of phase II was, let's be consistent in phase III. We're running two phase III clinical trials, very purposely. We're calling them X-TOLE2 and X-TOLE3 because, again, we really want that consistency with phase II. If you look at the inclusion/exclusion criteria in phase III, it's exactly the same. The studies are approximately the same size. Both X-TOLE2 and X-TOLE3, I'm just going to focus on X-TOLE2 because that's our first data readout, but they're carbon copies of each other. Inclusion/exclusion criteria is the same. Sample size is the same. Dose is the same. In phase III, we've got three arms to these studies, placebo and two active doses, 15 mg and 25 mg. Just to give you a bit of an idea, if we take those phase II data and we think about it in phase III, just because of the robustness of the phase II data, at the high dose, we have more than 99% power at that primary endpoint, which is the MPC. That's the regulatory endpoint in the U.S. Now let's think about conduct. When we think about X-TOLE2, to answer your question, we've gone to a lot of the same clinical studies that we had success with in X-TOLE. A little bit more bias kind of on the U.S. sites versus X-TOLE3, and went back to a lot of the sites that we've worked with. These physicians, one, are familiar to us. Two, they're familiar with the molecule. Many of them continue to have patients on open label extension from the phase II program because we still have over 150 subjects that have been out more than three years of dosing. We have our first patients that have been dosed more than five years now. We have this huge amount of safety data. What we disclosed on our call just recently in our Q1 results was about this consistency. When we think about running a phase III program, there's a bunch of things that we're going to measure during the conduct of the study. We're going to look at the types of patients that we're enrolling. This is the period at the screening and baseline. That's pre-randomization. We can track a number of metrics during the double-blind period. We can also track the patients that have completed the double-blind and are going to open label extension. What we said on our call is that we're seeing this really nice consistency in the phase III program as we compare it to phase II. We can think about that in terms of patient demographics, baseline characteristics. We can think about that in terms of the rollover rate, which was close to 97% in phase II into open label extension. As we look at all of those metrics and we look across the studies that we're using and the investigators that have experience, we're very confident in the conduct of the phase III study. Got it. You recently reported a slight delay in enrollment in X-TOLE2. Just anything specific underlying that? I guess how confident are you in a potential early 2026 readout? I guess are there ways you could proactively accelerate enrollment in X-TOLE3? I know it's different sites, but you can kind of get that done expeditiously as well. Yeah. I mean, to be clear, our real focus, because it's the critical path to filing the NDA, is X-TOLE2, right? So we've had the opportunity to have more than one regulatory interaction from an end-of-phase II meeting and subsequent to that, to really be clear with FDA that the filing package at the time of NDA is going to be our phase IIb study, X-TOLE plus X-TOLE2. Obviously, we can use a lot of the safety data from X-TOLE3 as well. You're right, we've had a slight delay in enrollment, a slight delay to top-line data. We do feel confident that we're getting close to the completion of enrollment. We've said that enrollment will complete in the phase III program in the next few months and data in early 2026. In terms of trying to accelerate things, I think the most important thing is a well-run study, quality, conduct, all of the things that are critically important for the success at the end of the day, which we talked about a lot kind of in the first question in terms of the conduct that we're very comfortable with. We have spoken with investors a number of times over the years that these epilepsy studies do take some time. You do see some variability in those screening rates. You do see a little bit of variability even in the screen and baseline failure rate. Remember, every patient that's screened doesn't get randomized. Those patients have to have the appropriate number of seizures during their baseline period, and they have to meet a number of other criteria. We are seeing a little bit of a higher screen failure rate in phase III versus the phase II program. That means we have to screen a few more patients to get to the end. We are confident that we're getting close to the end of the study. Good. Sounds like you're in the home stretch. Kind of speaking of the focus being on X-TOLE2, because it's a critical path for regulatory, I guess, can you talk about some of your most recent regulatory interactions? Have you met with FDA since some of the changes in leadership? What's your sense as to, I guess, how have your interactions been? Any corroboration from kind of new leadership that the phase II plus the X-TOLE2 study can definitely be supportive of approval? Or is that something that's still going to be, I guess, finalized once you turn over the data card? Yeah. Overall, we have not seen a change in our interaction with FDA. I'll caveat that with it is early days, right? We are interacting with the FDA on a semi-regular basis, but obviously not all the time. As we get closer to the NDA, there will be more interaction. I expect more interaction through the remainder of 2025. Obviously, a lot of interaction as we get into 2026. Overall, at least in our interaction with FDA over the last couple of months, we have not seen a change in terms of the work we have been doing with them. Excellent. You mentioned the 150 patients you have in the long-term extension from the phase II. Can you talk a little bit more in terms of your most recent looks there at that database, what you've seen both on the efficacy side and then with regards to some of the AEs you might be looking for, pigmentation, urinary retention? What are you seeing there? Yeah. I think one of the real benefits of where we are in our program when I compare it to other programs out there and the amount of data that we're going to have, not only at the time of NDA, but at launch. I would say the profile of azetukalner and XCOPRI, and the profile of Xenon in the epilepsy community has been really driven by a lot of this open label extension data. If we go back and just talk a little bit about the history, this started as a one-year open label study in phase II. We had not yet unblinded the phase II data when we had a number of physicians, we were coming up to that 12-month period. A number of physicians were calling us saying, "I believe my patient's doing really well on open label extension. Can you provide drug longer than the 12 months? We had not yet unblinded the data. We always know even a study that may not be successful, there may be some individual patients that are having some benefit. Obviously, once we unblinded the data and saw how robust the signal was, I think that this is a very important medicine for patients. We took that one-year open label. Initially, we extended it to three years and then to five years. It is now a seven-year open label extension. All of those patients that are doing well on therapy continue to have access to drug. That has also given us an opportunity to cut the data once a year and be able to provide that to the medical community. Our last update was a three-year update. Even though we have patients that have been on the drug more than five years, every patient had the opportunity to go through three years of dosing. That is why I said we have just over 150 patients that have been on the drug more than three years. We did a cut of those data last fall. We had the opportunity to share that at the largest medical congress in epilepsy, which is AES, the American Epilepsy Society meeting that takes place in December every year. What we found on the efficacy side for those data is for those patients that had gone through three years of dosing, they had a one in three chance of being seizure-free for 12 months or more. I really want to put those data into context because it is quite a remarkable outcome. If we look at the baseline characteristics of these patients, the median patient in our phase II program had failed six drugs. They were on three background medications, and they were having 13.5 seizures per month for 28 days. Think about it as a seizure every other day. Now we're getting one in three of them going a year with no seizures at all. That year is critically important because that year generally brings a lot more independence to your life. In many states, you can drive again if you've been seizure-free for more than 12 months. The anecdotal feedback we're hearing from physicians is these patients are working more. They're having more social interactions. They're gaining more independence. I think it's really rewarding for the work that we do and the patients that we're helping. On the safety side of the equation, again, with long-term data, we get to really be able to understand the overall safety profile of the data. You've heard a couple of comments from us made over time, which is we see a consistency in the adverse event profile. We know as we push dose higher, that dose does provide more efficacy, but you do see more adverse events in a dose-dependent manner. We see the CNS adverse events that are very common with all anti-seizure medicines, some level of dizziness, somnolence, and fatigue. We see some adverse events at lower levels as well. That adverse event profile is consistent whether we look at in the double-blind period or over the open label period. We really have a huge amount of understanding on the profile of the drug, and we can really educate the medical community as we get ready for launch. You asked about two specific adverse events, about pigmentation and urinary retention. For those that do not know, the reason that Brian is asking those questions is there was a predecessor molecule before azetukalner called ezogabine. That drug was the same mechanism. It is no longer available commercially. That drug had a chemistry risk around pigmentation. Also, some of the patients did see urinary retention, and a very small number of patients needed to be hospitalized and needed a catheter. We have not seen any ezogabine-like pigmentation in any patient now, and we have over 700 patient years of exposure. We feel very comfortable in making the comment that what we believed was a chemistry-related ezogabine pigmentation risk has been addressed. On urinary, we saw two patients in our double-blind of a denominator of 211 patients on active dose. We have seen a couple of patients in open label extension. We have not seen any patients come off drug due to any urinary symptoms. We have seen a few dose reductions, but no one has come off drug. We have seen no hospitalizations. We have seen no medical intervention at all. I think the profile that we are seeing when we have a much more potent drug that is not renally excreted and has modestly a better selectivity profile as well, I do not think we are seeing the types of urinary events that we were seeing with ezogabine or with ezetucalner. I think the bottom line here, overall, we feel very comfortable with the adverse event profile. Great. Let's talk a little bit about the market opportunity in epilepsy. There's obviously a lot of polypharmacy in the space, but still, there's many patients who aren't getting good seizure control. Based on the efficacy and safety profile you're seeing, based on your conversations and feedback from KOLs, what's your latest thinking on where Azetukalner might slide into the treatment paradigm? Are there any learnings you can take from some of the recent branded launches? I know there are different profiles and different mechanisms, but launches like XCOPRI, which have gone reasonably well. What can you take away from that that might shape your commercial strategy? Yeah. I mean, if we start at the highest level and just look at epidemiology, there's about 3 million Americans that have epilepsy. 60% have focal onset seizures. So call it just under 2 million patients. And we think about 50% of them, 30-50% of them are not getting good seizure control. So we think those are good candidates for, as you mentioned, polypharmacy and having access to a branded agent. When we add in some of the adolescent and pediatric patients that have focal seizures as well, call it in rough terms about a million patients in the U.S., I think, is probably the addressable market for a drug like Azetukalner. The medical practice and commercial payer environment are really well aligned here. If you're a newly diagnosed patient, you're going to get a monotherapy, and you're going to get a generic drug. You'll get a drug like levetiracetam, Keppra, maybe a drug like lamotrigine or lacosamide. We're seeing more lacosamide usage now that Vimpat went off patent a couple of years ago. Those are kind of the drugs that you're going to have really high scripts. For patients that are doing well on a generic drug and a monotherapy, that's good. That's great. We know a lot about those molecules. As we have patients that are having breakthrough seizures or they're having tolerability issues, and we're starting to introduce polypharmacy, call this at either a second or kind of third line, that's where we're going to see the introduction of a branded medicine. I think that's the opportunity for azetukalner. If we think about the profile of azetukalner versus some of the other launches, there's been some very successful drugs in epilepsy, in focal onset seizures. Keppra comes to mind, Lamictal, Vimpat, those have all been multi-blockbusters. As you mentioned, the most recent branded drug is XCOPRI, or cenobamate is the generic name. They're guided to they'll do about $400 million-$450 million in sales this year. SK Life Sciences believes that's going to be a billion-dollar drug by the end of the decade. I think we would agree with you. I think that launch has been fine. It was challenging in the early days and launched during the pandemic. Over the last couple of years, the growth in that has been good. I think that's an important medicine to be available for physicians and their patients. I do think azetukalner has some real benefits over XCOPRI. XCOPRI has to be titrated over 12-16 weeks. You are not on a therapeutic dose on day one. There are a number of DDIs associated with that molecule as well. Not only are you increasing the drug over time, but you may have to adjust other drugs that are being used in polypharmacy. What we know with azetukalner is there is no titration. You are on your therapeutic dose on day one. We see early onset to efficacy. Remember, in the phase II program, we were statistically significant at week one, which is something that we are going to measure in phase III as well. We potentially have mood benefit also. When we just look at the attributes of azetukalner, whether we compare it to XCOPRI or a number of the other drugs that have been used either currently or in the past, I think the profile of azetukalner really shows up very well. Okay. Great. Maybe shifting gears to major depressive disorder, you guys recently revealed some new data from an investigator-sponsored study, the Mount Sinai study of Azetukalner in that indication. Obviously, a small single-site investigator study, but you did see some, there were some treatment effects observed there. Can you talk a little bit about just how those data impact how you're seeing the likelihood of success of your studies, if there's anything, any new learnings there that would impact your overall either study design or kind of how you think about positioning of the drug? Just remind us, I know you alluded to this a little bit on your earnings call, but maybe in a little bit more detail on how the tolerability profile in the Mount Sinai study compared to what you saw in Xenova, because that's one of the biggest questions that we get is just how the CNS side effects line up relative to other treatments for MDD. I think everyone's very convinced about potential benefit-risk equation in epilepsy, but maybe less sure given that there's more options in MDD. Maybe you can walk us through the Sinai data. Yeah, all good questions. We have had an interest in this mechanism in depression for a few years now. It is really some of the pioneering work that the collaborators at Mount Sinai did, both preclinically and trying to understand the mechanistic rationale. They also did some of the early work on Ezogabine in major depressive disorder as well. I always put more weight on a company-sponsored study than an IST. I think that is probably a consistent view. Just as a reminder, about 18 months ago, we had our phase II Xenova study. I am going to bias my comments a little bit more. I will comment on the IST, but I am going to bias my comments a little bit more to our Xenova study just because it was significantly larger than the IST. We had two active doses. At least we can think about a dose response. It was really those data where we saw this consistency in terms of separation between active and placebo, looking at both clinical scales of depression using MADRS as well as HAMD-17 and this clinical scale of anhedonia, called SHAPS, right? I think we saw really nice data. I think the side effect profile was milder than we saw in epilepsy. In that study, we did see a dose dependency both in efficacy and in the adverse event profile as well. We looked at 10 milligrams and 20 milligrams. It was really those data that drove us to run a large phase III program in MDD. The IST data, although I think interesting and we'll talk about it, was not decision relevant for us in terms of the phase III program in MDD. To that end, we've already started the phase III program. We started our first phase III MDD study, which we call X-NOVA2, a few months ago. How's that going? It's going well so far. Still early days. But so far, the study is meeting our expectations in terms of execution and the types of patients that we're enrolling. We'll have the second phase III MDD study, which we're calling X-NOVA3. That'll start in the next couple of months. We're also going to start a phase III program in bipolar depression. That'll also start in the next couple of months. We're going to have an incredibly large and robust phase III program in psychiatry, both in MDD and in bipolar depression as well. In the IST, so the IST, small number of patients. It was only about 30 subjects per arm. It was a single dose at 20 mg. The primary endpoint was actually not a clinical scale. It was a functional MRI endpoint. It didn't look like there was separation on the functional MRI endpoint. What we've said in terms of the clinical scales of depression, they use MADRS as the scale. As a reminder, in our phase III program, we've moved to HAMD-17. I think there's some really good reasons on why we changed to the Hamilton scale. They looked at MADRS, and then they looked at the scale of anhedonia, which is the SHAPS scale. They had some other exploratory endpoints as well in terms of some of the clinical global impression scales. What we were able to say on MADRS and on SHAPS is that the 20 milligrams outperformed placebo at every single time point. I wouldn't say that this was a well-powered study, so we didn't see significance, but we did see separation at every point. We saw the greatest separation on the clinical scale of depression at week 6. We saw a little bit of that separation come back together at week 8. Do you worry that might be tachyphylaxis or just variability? No, I yeah, we're not concerned about tachyphylaxis at all. I mean, we now have so much data with this molecule and this mechanism, both in epilepsy and depression, that we do not see any change in the signal over time. Actually, I think our epilepsy open label data, seeing how robust that is in the long term, is that we're not seeing any change in the signal. We actually know because we've seen the patient-level data, and we said this on our earnings call, it was actually caused by a couple of patients that had quite significant changes in their scales between week 6 and week 8. That is quite frankly just the challenge of a small study, right? An academic study at that. On the adverse event profile, yeah, I think one of the important things in terms of adverse events in depression, I agree, we need to be well aware of that. Important, we have not seen with this mechanism through multiple studies, any material changes on weight gain and any sexual dysfunction. I think if we think about standard of care in depression, I think that is really important that we have not seen that. Overall, in the IST, the adverse event profile was consistent with what we have seen in other studies. We are seeing the same types of adverse events. In terms of kind of their mild and moderate, there was one SAE that was in the drug arm. It was deemed unrelated. It actually happened 45 days after the last dose. It is not something that we are concerned about. If we look at the overall. What was that? Sorry? What was the SAE? The SAE, I do not think we have disclosed. James, Dr. Murrough, I think he will disclose in a couple of weeks. As I mentioned, it was weeks and weeks after the last dose. It was deemed unrelated. It was not something that we were concerned about. Some of the adverse event in terms of the rates, some are higher than we have seen in the past, some are lower. That is, again, I think just the law of small numbers and small sample size where you do see more variability in the data. Maybe in the last 30 seconds, because I know we're bumping up on time, but there's a lot more in the pipeline and that pipeline is starting to mature in pain, epilepsy, other syndromes. I think you've talked about having an investor day later this year where you're going to talk about that in a little more detail. Anything you can sort of quickly preview there and what we should be looking for, what you're most excited about? Yeah, I mean, yeah, I'll be really, really brief. We're incredibly excited about the portfolio of targets we're looking at. Those are maturing now. We have the first of those, which is a Kv7 drug called XEN1120. We're just in a phase 1 clinical trial now. We'll get Nav1.7, a drug we call XEN1701. That'll be in clinical development in a couple of months as well. That discovery portfolio is maturing nicely. As you mentioned, we're going to do at least two investor kind of webinars later this year, one focused on Nav1.7 and Kv7 in the treatment of pain and really understanding that from a mechanistic perspective and the profile of our molecules. We're very excited about a program we have on a target called Nav1.1. We'd like to do a little bit of a deeper dive with the street on that mechanism and some of the early preclinical data that we've generated as well. Good. We're out of time, Ian. Thanks so much. Great to have you here. Thank you, Brian. I appreciate it. I appreciate it.