Hi again, everyone. I'm Brian Abrahams, senior biotech analyst here at RBC Capital Markets. We're really pleased to have our next featured company, Xenon Pharmaceuticals, represented by their President and Chief Executive Officer, Ian Mortimer, and their Chief Financial Officer, Tucker Kelly. Ian and Tucker, thank you guys so much for being here. Thanks, Brian. Thank you. All right, it's been a really exciting year so far for you guys, with some of the data we've seen from azetukalner in the X-TOLE2. Yeah phase III, focal onset epilepsy study. The data that you released in March demonstrated very impressive efficacy at 43% placebo-adjusted seizure reduction at the highest dose. You got to 7% of patients that, to complete remission. What's been the reactions that you guys have been hearing from KOLs following the data? How are you thinking azetukalner will ultimately be positioned in the treatment paradigm now that you've had a chance to kind of sit with the data for a couple of months, hear this feedback, digest some of the details? Sure, yeah. Great way to start. I'll take a look, a little bit of a step back and just give a bit of context on azetukalner and epilepsy, talk through the phase III data. I think you've set it up really nicely. The benefit we had is only a few weeks after data, we were at the American Neurology meeting, AAN, in Chicago, where the data were presented at the podium. We had this fantastic opportunity to talk with a number of KOLs, both on the epilepsy side, but as I think a bit of a theme that you'll hear from us is that the profile of azetukalner we think is going to do really well in general neurology as well. There's a number of those prescribers that we're getting to spend more time with and give them, you know, an update on the profile of the medicine. azetukalner, this is a Kv7 drug, it affects a potassium channel in the brain, which really is a brake on hyperexcitability and can have a benefit on these seizure disorders and epilepsy. You walked through the data on a placebo-adjusted basis. We had really strong phase IIb data, the X-TOLE study a few years ago, we were trying to replicate those data with X-TOLE2, which read out in March, as you mentioned. Actually, we were surprised because the X-TOLE2 data outperformed the X-TOLE data, I think it's rare when you move from phase II to phase III that the data get better. Yeah. Actually, you and I spoke a lot about this, and you did some fantastic research looking at other epilepsy drugs and how they did from phase II to phase III and, you know, consistency. You expected that effect size to probably come in a little bit. Yeah. Actually, we went the other way. The effect size got bigger from phase II to phase III. We're now in this incredibly fortunate position where we've got a drug with a novel mechanism. You know, there are a lot of drugs to treat focal onset seizures. Over 20 drugs are approved. Actually, there's not a lot of mechanistic diversity. Most of those drugs fit into a narrow number of different mechanisms. There are no potassium channel modulators on the market to treat epilepsy, so we're bringing a novel mechanism. We now have in 2 studies the best placebo-adjusted efficacy ever seen in focal onset seizures in a very refractory population. If you go back and look at the other studies that have been done historically, it's usually in a population that has either failed fewer drugs or had less baseline seizure burden, whereas we had a patient population where these patients had failed a number of therapies. The majority of patients were on 3 background medications, and they were still having a seizure every other day, so it was quite a refractory population. About 60% of them, this was a big change as well, about 60% of them were either on or had failed cenobamate, and that was a big difference from phase II to phase III. Still, we got this incredibly strong efficacy readout. We have a novel mechanism. We have incredibly strong efficacy, both in the double-blind period, but also in open label extension. The drug doesn't need to be titrated. It's 1 pill once a day. You're on your efficacious dose on day 1. We don't have meaningful DDIs with other ASMs. When you look at this package overall, it's a package that we don't believe has really been brought forward to the prescribers in quite some time. We had the opportunity at AAN, the chair of our steering committee for X-TOLE2, Dr. Jacqueline French, that many, many people in the audience know very well, she presented the data at AAN in a podium late-breaking science presentation. We had an opportunity to interact with a number of KOLs and a number of general neurologists. The feedback is incredibly strong, which you would expect with a profile of a molecule like this, is that I think there's a number of patients, and Tucker can walk through the epidemiology and the number of patients that still are having breakthrough seizures that need better, better medicines. So the feedback from the KOL community is they're looking for a novel mechanism. They're looking for a drug that can provide good efficacy both in the short term and the long term. Probably the difference between the specialist, the level 3 and level 4 epileptologists, and the general neurologist is the general neurologist really biases to the ease of use. Yep. Not having to do monitoring, not having to have drug interactions, not having to titrate the drug, and having the novel mechanism and the efficacy is things that resonate really well in the general neurology community that are, you know, experts, but not epilepsy specialists. The ability for them to keep their patients longer and not have to refer them on to the level 3 or level 4 center is, I think, where the drug's gonna do really well, both in the specialist community as well as in the general neurology community. Yeah the overall patient population. Yeah. Yeah. The epi tells you there's about, you know, 1.8 million FOS patients in the U.S. There's another about 900,000, you know, patients that have generalized epilepsy, PGTCS, which is subject to another study that we're running in phase III. For those FOS patients, the good news for them is that a lot of them are well controlled with existing medications. They'll go on usually a monotherapy to start with an SV2A or sodium channel blocker, and then maybe if they do progress, go under a second monotherapy. For good half of those patients, they do well. What we're gonna be going after are those patients who are either partially uncontrolled or significantly under control. As we saw in our study, as Ian mentioned, these patients have gone through and cycled through 5 or 6 prior anti-seizure medications and are on 2 or 3 concomitant meds. You know, there's a heavily pretreated portion of the population. Our goal, both within the epileptology portion of the channel as well as in the general neurology, is to certainly start there but move upstream rather quickly and try and get this medicine with the novel MOA to the point where it's gonna be used more frequently as one of the earlier add-on therapies. We're not looking to go frontline. This isn't gonna be something that we're gonna, you know, displace Keppra in de novo patients who've just been diagnosed. We think it has the opportunity, given all the attributes that Ian outlined, that it can be a really significant impact for physicians and patients quite early in the treatment paradigm. That's really helpful. I guess, You guys have talked about filing sometime this summer. Yep. Can you talk a little bit more about maybe the overall status there? What more needs to be done? How have your conversations gone with the agency, and to what degree do you expect some of the changes in FDA leadership will impact that? Yeah. We've had a great relationship with the agency thus far. We've been really communicative with them as they have with us throughout the development of azetukalner. And the team's working really hard to get the dossier put together for the submission in Q3. Good news is we've got a lot of data that we're able to do in advance of getting the readout from X-TOLE2. A lot of the nonclinical portions of the submission, around CMC, were already kind of ready to go. The real lift now is with the X-TOLE2 data, getting that integrated safety summary, which is a key component and a more complicated piece that integrates the safety information both from X-TOLE, the original phase IIb study, X-TOLE2, the phase III, and then we've got a number of other open label studies. There's a lot of safety data, which we think is great. It's a huge package of information, a really consistent and supportive database of efficacy and safety. For the safety side, you know, you do additional cuts of that safety data for the initial NDA submission. Team's working really hard. It's going really well. We'll have our regular interactions with the FDA. We'll obviously have a pre-NDA meeting. Again, given the strength of the data and the ongoing dialogue we've had with the agency over time, we're not at all worried about that. We think it's gonna be a good meeting with them, and look forward to getting the submission in later this year. Excellent. Speaking of the open label data, I guess When could we expect to see additional data from the X-TOLE2 open label extension? Maybe just how has that overall been tracking so far relative to what you've seen now over obviously a longer period of time with the X-TOLE. Yeah open label? Yeah. I'll talk a little bit about the X-TOLE open label first, and then we'll get to your question on the X-TOLE2 open label. In X-TOLE patients, there was an 8-week double blind, then patients had the opportunity to go into open label extension. We had a 97% rollover rate, really high. That was consistent in the phase III program as well. Rollover rate, excuse me, about the same, in the high 90s, for the patients that finished the X-TOLE2 double blind period. We have this real richness of data from the X-TOLE open label. All patients have been through 4 years of dosing. We've actually continued to extend that open label. It started as a one year OLE. We extended it to 3, 5, and now it's a seven year open label. That's really because the patients are doing remarkably well, and it's the right thing to ensure that these patients continue to have access to the medicine. What you see at the American Epilepsy Society meeting every year is we mature that open label data by a year. Yeah. We had the 48-month cut data last December. Coming up this AES in December of this year, we'll have a 60-month cut of the data. What we're finding for those patients that have been on the drug for more than four years, almost 40% of them are getting at least 12 months of seizure freedom, and that's actually quite remarkable if you think we've walked through how many drugs these patients had failed, the background medications, and they were having on average a seizure every other day. Now we have this subpopulation that is going six months or 12 months with no seizures at all. That can be game changing in terms of work, school, driving, et cetera. Exactly. In most jurisdictions, if it's 12 months, then you have the opportunity to drive again. You know, we get feedback from physicians that these patients are seizure-free for the first time in their lives. Yeah. A massive impact on their independence. The other data cut that we did, which to our knowledge hadn't been done before, at AES a few months ago, is we looked at those patients that had seizure freedom and then lost it and whether they could regain it again. You can have a breakthrough seizure for a lot of different things, right? It may be in a, you know, a missed medication. It could be an impact on your life in terms of sleep or a stress or something else that's changed in your life, and you have a breakthrough seizure. What we found for those patients that had a breakthrough seizure, that the vast majority of them can regain long periods of seizure freedom even after that breakthrough seizure, and I think that was an analysis that was really relevant as we think about how the medicine's gonna be used in the real world. That was really well received. So we'll have more open label data from X-TOLE. Your question specifically on X-TOLE2, we need a little bit more time. We need that data to mature. We're not gonna have X-TOLE2 open label extension data at this AES, but I'd expect as we get into 2027, 2028, you'll start to see some of the open label data from X-TOLE2 as well. Okay. Given everything we know about the medicine, the rollover rate, our expectations is the X-TOLE2 open label data will track what we've seen in the X-TOLE open label. Good. You talked about just the size of the market and the unmet need amongst patients who are still having frequent breakthrough seizures. Tell us about some of the pre-launch activities and how you're planning to move into the market. I guess on one hand, I'm sure this is a highly specialized market. You have a unique offering with a differentiated MOA. You know, on the other hand, you know, you mentioned that general neurologists, I imagine, who see a lot of these patients, I imagine it's a bit more diffuse, and there are a lot of generics and other medicines in this space. When you sort of think about all those considerations, what are you guys doing today in order to lay the groundwork and foundation for a good launch? Do you have a sense at this point, based on your market research, what sort of a target overall sales team size might look like? Yeah. Brian, I joined about 6 months ago from another company that was in the commercial space and targeted oncology world, and one of the things that was really impressive about what Ian and the team had built at Xenon is that we were doing those investments on the commercial side even before we had gotten the X-TOLE2 data. We've had MSLs out in the field, almost 10 at the time, almost 12 now, for the last 18, 24 months out there talking with KOLs and physicians, starting that dialogue with them, and building the infrastructure and that core substrate for the commercial team. We've had folks that are focused on market access for a while now. We built out the senior leadership team. I think we had a lot of things in place even before we get to today and kind of the march and the sprint toward the launch of the drug. We've got a really good foundation to build on, and the team will be doing more between now and the actual approval date to get ready. We can talk a little bit about kinda what some of those things are, but I think we put in place a infrastructure that will build out with a field force in the U.S. that'll be around 75 or so reps. The total commercial FTEs will be probably in the 150 or so range. We think that's gonna be a great size for us to be able to try and penetrate both the specialists, the epileptologists, there's about 2,400 of those in the U.S. There's obviously a lot more general neurologists. There's about 18,000. We're not gonna be going after all 18,000, at least on a personal promotion basis, at the outset, but we are gonna have a focus group of probably another 5,000-6,000 of those. We think the 7,500-8,000 physicians will be our kind of our core target population, comprised of those epileptologists and then a really targeted group of general neurologists that we think either write branded medicines today, see more epilepsy patients. 'Cause again, where we think this can be a really big drug, is getting it not only to the epileptologists who see, you know, per capita a lot of patients and see some of the more difficult ones, but getting it out into the general neurology community. Ian talked about before the attributes that azetukalner brings, we think are gonna be great. All those things about ease of use, that they bias toward will be really helpful for those physicians to try and take up the adoption. That's what we see in other ASM launches in the past, that we think is different with azetukalner, and so we're building that infrastructure to be able to try and get there quickly. Got it. Speaking of ease of use, what doses would you anticipate will be on azetukalner's label, in order to enable physicians to optimize and individualize- Yeah the dose for each patient? Yeah. I think the back half of your question is super important, right? Yeah. Not every dose is going to be the right dose for every patient, and we need that flexibility. The discussions we've had with the agency to date have been to have 4 doses on label, 10, 15, 20, and 25. In our phase II study, X-TOLE, we had it was a dose-ranging study where we looked at 3 doses of the drug, 10, 20, and 25. All doses were statistically significant on that primary endpoint of the MPC or the seizure reduction. Clear dose response. If you remember those data, we went from 10 to 20 to 25, almost linear. Yeah right, where you had a reduction in seizures. In the phase III program, we've looked at two doses, 15, which was a new dose, and 25 mg as the top dose. Again, saw a clear dose response. Actually, we have this really nice graph that we show of all four doses over the two studies, either eight weeks or 12 weeks of dosing. You can see two really key themes. One, there's a key dose response. Yeah. 2, there's a time-based deepening of the response, right? That if you move from the 8 weeks, which was the double blind period in X-TOLE, to 12 weeks in X-TOLE2 at the same dose, you have a better response at 12 weeks than you did at 8 weeks. If you look at our open label data, it then pulls through in the longer term as well. It looks like the response deepens 3 or 4 months after, and then again at about 5 or 6 months, and then again at about 12 months. That population in open label is having about a 90% reduction in their seizures overall. It does look like, and we don't have a good mechanistic rationale for this, but it does look like patients do even better the longer they're on therapy. Yeah, our discussions with the agency is to have all 4 doses on label. Although all are efficacious, likely not every dose is gonna be the right dose for all patients. Often we get a question, "Well, where do you think the general- Yeah patient is gonna start? Yeah. I think it's gonna depend a little bit on the background of that patient, what types of seizures they're having. One of the things that we haven't yet shown in the X-TOLE2 data, but we did in X-TOLE, is we talk about these patients as having focal epilepsy, but there's actually a number of different seizure subtypes they can have. One of the more concerning seizure subtype is a focal to bilateral. So it's a primary diagnosis of a focal seizure, so it starts in one hemisphere of the brain, but it can move to both hemispheres as a secondary generalization. Yeah. This is a focal to bilateral tonic-clonic seizure. When you're having those tonic-clonic seizures, there's a greater risk of injury and actually a greater risk of death, which is called SUDEP. Yeah. We showed in the X-TOLE data, in X-TOLE2 to come, we'll show some of those data later this year at AES, is that specific seizure subtype patients did really well. A really good reduction in their focal to bilateral generalized seizures gives us confidence in our primary generalized tonic-clonic seizure study as well. Again, patients that are having a certain seizure subtype, you may want to start at a higher dose. Overall, we think that most physicians, when we get feedback, will probably start at 15 mg. That's an efficacious dose, and it's a dose that's really benign from a safety point of view. Yeah. If you remember those AE tables, from our phase III program, the 15 mg looks very much like placebo in terms of the AE profile. A little bit higher dizziness in 15 mg versus placebo, but everything else very comparable, when we look at the 15 milligrams versus placebo. That's probably a really good starting dose. With breakthrough seizures, that's a good tolerated dose, then the opportunity to move up either to 20 or 25 mg. Got it. Thinking about potential speed to market, based on your initial FDA feedback, do you think priority review is a realistic opportunity? Is that something you're planning to apply for? Yeah. We think the drug has got an exceptional risk-benefit profile. Yeah. We think it brings a lot of efficacy to patients. The reality is the landscape of ASMs in the past will tell you that priority review is not something you see with the approvals there. Our base case- Okay Going assumption is that we would have a standard review for the drug. Okay. Look, we'll always continue to be the best advocates for the drug that we can. We think it's got a great profile, we'll have discussion with the agency. Okay is a standard review. That's useful. You've seen broad antidepressive effects, in an MDD study. You've talked about, you know, some hints of effects in X-TOLE2 as well. Yep. I guess, can you remind us kind of where we stand with the ongoing phase III program in MDD, and how you're thinking about positioning this in the MDD landscape versus just really having that, the attributes of mood benefits to further enhance the FOS label? Yeah. Let's start on the psychiatry side. We read out a POC study called the X-NOVA study 2 years ago in patients with major depressive disorder, where we saw a clear separation between active and placebo on both clinical scales using MADRS as well as HAMD-17. Nominal p-value is less than.05 on HAMD-17 and on SHAPS. We also saw early efficacy. We see this both in epilepsy, we see it in psychiatry, where the separation, you get that separation early. We also saw a dose response. 10 mg was better than placebo, 20 was better than 10 mg in that X-NOVA study. That gave us confidence to go into a phase III program. We have a large phase III psychiatry program ongoing for azetukalner, 2 ongoing phase III clinical trials in major depressive disorder, X-NOVA2 and X-NOVA3, and then we started a study in bipolar depression that we call the XCEDE study. First phase III psychiatry readout will be X-NOVA2, and that'll be in the first half of 2027. We've made really good progress on that study. You know, a little bit different than epilepsy, a few things that I think are important when we speak to the prescribers on the psychiatry side. One, again, still a reasonably narrow number of mechanisms available for psychiatrists. Bringing a novel mechanism, there are no potassium channel modulators to treat either epilepsy or depression, I think is gonna be important. Two, the early onset to efficacy is actually probably more important in psychiatry than it is in epilepsy. In epilepsy, these patients have had the disease for many, many years. Absolutely, they wanna get their seizures under control, but they're thinking about it, the physicians are thinking about it over a longer period of time. With psychiatry, if you're in a major depressive episode, you wanna help that patient immediately. The SSRIs and SNRIs can often take weeks or months to work, an opportunity to have an antidepressant effect so that we see separation at week 1 could be very beneficial. Novel mechanism, early onset to efficacy, a different side effect profile. One of the benefits of azetukalner in psychiatry is we don't see the sexual dysfunction or side effects or the weight gain that is seen with some of the current standards of care. Again, a differentiated safety profile and potentially the impact on anhedonia. Yeah. These patients can often, are doing better on their depressive symptoms but still are anhedonic. The opportunity to have a mechanism that could have an impact on anhedonia could be very positive as well. That's the feedback we get on the psychiatry side. It's a little bit different than on the epilepsy side. I know we have just a minute left. Yeah I'd be remiss if I didn't touch on. Sure 'cause I know that's an emerging program, but as, you know, having followed you guys for. A long time. over a decade now, I know that that's something that you guys were really originators on in terms of ion channel biology. Can you it sounds like what you're seeing from both the Nav1.7 and the Kv7 early stage candidates for pain has been encouraging in the healthy volunteers. I guess, can you talk a little bit more about, I guess, what you're seeing, when we might see additional phase I data, and, like, just maybe outline preliminarily what, where you see these moving forward, acute versus chronic, and what indications? Sure. I know that's a lot, but maybe if you could. I'll- a 1-minute summary. Yeah 'cause I want to make sure. For sure. we cover that. We've got 2 phase I studies ongoing, XEN1701, this is a Nav1.7 inhibitor, XEN1120 is a Kv7 channel modulator, both in healthy volunteer studies. As you mentioned, both we have reached exposures in humans where we believe we would see an efficacious outcome in a proof of concept study. In Nav1.7, it's more about the receptor occupancy that would mimic the human genetics, so we're seeing those levels of exposure already. On the Kv7 side, enough exposure where we're seeing preclinical efficacy and believe that our model would suggest the exposures that we need to see in a human. In our phase I studies, the phase Is are not complete, but we're already at levels that give us confidence to move into phase II proof of concept studies. Those phase I should wrap up later this year, and then we'd be in a position to start those phase II proof of concept studies. Today, those POC studies would be in acute, so either a bunionectomy or an abdominoplasty. Both mechanisms don't necessarily say that we should go either into acute, chronic, nociceptive, or neuropathic, so what you'd expect from us is a broad development program to interrogate both of those as we move forward. Excellent. I know we're out of time. Ian and Tucker, thank you guys so much, look forward to talking again soon. Thanks. Great. Thanks again. Thank you so much. Great. Thank you, Brian.