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Hi, everyone, and thank you for joining us at our 2026 TD Cowen Neuropsychiatry Summit. I'm Jotho. I'm one of the senior biotech analysts here on the team at TD Cowan, and it is my pleasure to have with me today two members of the management team from Xenon. We have President and CEO Ian Mortimer, and we have CFO Tucker Kelly with us today. So thanks, guys, for joining me. Thanks for joining us, and thanks to the investor audience. Investors, if you do have questions, please feel free to throw them in your chat box, and we can try and work those into the discussion. But maybe, Ian, if you want to start off just a little bit at a high level, maybe touching on the progress of the company across 2026 and maybe what we should be looking for. And then, obviously, we'll touch on the update from last week as well, but maybe at a higher level you can just kick off. Yeah, that'd be great. Thanks, Joe, and thanks very much for hosting us, and good afternoon, everyone. So as we've talked about in the past, there's really three parts to Xenon right now that we spend a lot of time with investors on. the lead molecule is that to counter in epilepsy the expansion of is that you counter into the psychiatry program and then i think we have a really interesting and evolving and maturing early stage portfolio we've put three molecules into phase one studies over the past 15 months and i can touch upon those as well i think obviously we'll spend a lot of time on the psychiatry programme through q a so maybe on the overall remarks i'll i'll focus a bit more on epilepsy in the pain portfolio and then we can go a little bit deeper in psychiatry So obviously, we've made tremendous progress this year in epilepsy. You know, as Etu Kalner, we had incredibly strong phase 2B results a few years ago from the XTOL study. We were really trying to replicate that in XTol 2. Those results were released in March, and we exceeded, I think, all expectations, our internal expectations and your expectations, Joe, and others on the street, where we had this incredibly robust separation between 25 milligrams and placebo. actually the best placebo-adjusted efficacy we believe has ever been demonstrated in a focal onset seizure study. And so since March, we've really been working to get the NDA filed, and that's what we announced last week. So we filed our very first new drug application for a Zetucalner in focal onset seizures, obviously backed by two robust randomized placebo-controlled studies, X toll and X toll 2, incredibly strong efficacy, a really well understood safety and tolerability profile. And so a couple of things now, obviously we'll, we're now, we'll get into the FDA review process. The other update that we had last week as it relates to epilepsy is just how much exposures we have, how many exposures мы have. So we announced that we have 1500 patient years of exposure in epilepsy. Obviously the double blind are eight or 12 week studies. We have a significant amount of data in open label. So from XTOL, we now have patients that have been on the drug more than five years, and XTol2 patients are also on open label, really exciting. We'll have an update at the American Epilepsy Society meeting in December of this year, as we mature that XTол open label data another year, it'll now be 60 month data. And the efficacy in the long term, obviously, we're seeing really strong seizure reductions. And we're seen these longer periods of seizure freedom, which is really important for these patients. And then as we think about preparation for commercial, we hired Darren Klein as our chief commercial officer. He's built out his commercial leadership team. And they're really excited as we think about there hasn't been a focal onset seizure launch since 2019. This is a novel mechanism. Really, we haven't seen enough innovation in epilepsy in the more common forms of epilepsy like FOS. So we're bringing a novel mechanism. We've talked about the profile from an efficacy and safety point of view. And then just for the general neurologists, and Joe, you and I have talked a lot about this, you know, we think this is going to be an important medicine for the specialists, the epileptologists, but also for the General Neurologists. And that's because of how the drug is used. It's one pill once a day. We don't have to titrate the drug and really no risk on the DDI side. And so you don't Have to back titrate other medicines. So when we think about that overall profile, we think it's going to be really successful in epilepsy, and we're excited to get through the FDA review process and get this drug available for patients. As I said, we've been expanding his etch-a-counter into psychiatry. We had an update last week, which I know we'll go into. We're getting close to the Exnova 2 data, and мы have decided to wrap that phase three program up. We'll talk about that, and We'll Talk about the pause that we've had in the rest of the program. So I know you'll have a bunch of questions there, and we'll get to those. And then in the pain portfolio, I think we've made tremendous progress. We think, you know, novel analgesics and non-opioid pain medications is a tremendous opportunity. Our lead programs are just finishing phase one. One is a NAV1.7 molecule, an inhibitor called XCN1701, and then we have a KV7 drug called XN1120. Those will be in phase two proof of concept pain studies next year. And then we have another 1.7 molecule that just went into phase one. So I think you're going to see more data from our early stage portfolio as we head into next year? Perfect. Excellent. Great, great start. And then, yeah, I guess just given the topic of the day, we'll start maybe on the neuropsychiatry things with the update from last week, obviously indicating that you're seeing some AEs that are not atypical to asepticoliner itself, but in the context of, you know, MDD and BPD, you know, led to the pause here. So maybe can you just walk us through sort of the timeline cadence of what led to the pause and maybe what you know and what you don't know, because obviously still the data are blinded. So, you know, kind of what do we know about these events and maybe what don't you know yet? Sure. Happy to provide an overview and then we can go a little bit deeper in some of the Q&A. So maybe just even before we get to last week's announcement, I think it'd be helpful just to take a bit of step back. What was the history of this molecule and this mechanism in psychiatry? And then kind of bring us forward to today. I'll give some updates on what we talked about last week. And then obviously, we've had lots of investor engagement over the past number of days. And so I'll kind of weave through some of the questions that we're receiving and some perspective on that as well. obviously this mechanism is well understood in epilepsy and and that's been a huge part of our development we really believe the opportunity for potassium channel modulation has good rationale in both major depressive disorder as well as bipolar depression and so we started a number of years ago to start testing that hypothesis that started with a phase two proof of concept study in major dep expressive disorder called the ex nova study i would have called that more of a proof of concept, so a little bit smaller in terms of the sample size, just over 50 subjects per arm. We looked at 10 and 20 milligrams versus placebo, so, a three-arm study. Those data were available a couple of years ago, and we found, I think, some interesting conclusions from that study. Number one, we saw a clear dose response, so 10 milligrams separated from placebo and 20 milligrams separated from 10 milligrams. We saw a clear dose response. The primary endpoint was a clinical scale of depression called Madras. One of the secondary endpoints was a different scale of depression, called HAMD17. And the reason I mention that, that's the endpoint we're using in phase three. This mechanism also, we believe, has the opportunity to have an impact on anhedonia, which is an important comorbidity for these depressed patients. And so we looked at an endpoint of anhedonia, which is measured on a scale called SHAPS. So out of that study, we believed that we had clear drug activity, clear separation, and a dose response. And we believed we had all of the information to design a phase three program. That was on the efficacy side on those key endpoints. On the safety side, the safety of azetucaliner in that ExNova study, it was really well tolerated. It was better tolerated, again, a cross-trial comparison, so the caveats that come with that, but it looked like it was better tolerate in that MDD study than what we were seeing in the epilepsy studies. That was a surprise to us at the time, and I think it was a surprised to people outside the organization as well, but obviously that was part of the decision-making as we moved forward. So we're now in a large phase three psychiatry program. We have two phase three MDD studies, Exnova 2 and Exnova 3, and we have an ongoing bipolar depression study, which we call the EXCEED study. So, we initiated these studies. Exnova2 was about 18 months ago, Exnova3 last year, and EXCEed a little bit more recently. And so, now we've got overall kind of hundreds and hundreds of patients that have been enrolled in that phase three program. Just like normal drug development, we're looking at blinded data on an ongoing basis, and we're sharing those data also with a DSMB just in kind of the normal course of running those studies. And really one of the kind of emerging profiles in phase three is that the safety in the phase three psychiatry program is starting to look more like the phase three epilepsy program and probably a little bit and a little bit different than what we saw in phase two. And I'll go into a little bit more detail there. So, you know, this is a very potent mechanism and a very potent drug in terms of reducing hyper excitability in the brain. And what we find is that the safety profile is really well understood that there is a dose and exposure relationship here. So we have some more common adverse events, things like dizziness and somnolence. These are very common adverse events for anti-seizure medicines. And then we have some adverse events that are less than 10%. They do show up, but they're less common. And those are some of the adverse events that we talked about last week. We kind of put them broadly in the category of neuropsychiatric adverse events. So it may be some confusion or concentration, aphasia, word finding. And then we have some very rare adverse events, and SAEs are quite rare as well when we think about the overall profile. But as this adverse event profile was really being evaluated in phase three, in discussions with a regularly scheduled DSMB meeting, the discussion was, can we improve the tolerability profile in psychiatry? And so the decision was to pause the study to see if we can incorporate changes in dosing, and we're really focused on dose escalation. And we believe that based on data that we have available to us, that that'll improve tolerability. As part of that discussion and decision, as a sponsor, we were looking at the totality of the data package, and We've made excellent progress in Exnova 2. That study was more than 80% enrolled, really well-powered. And so anytime we want to have a discussion around expanding the therapeutic opportunity for a medicine, in this case, is that to counter from epilepsy into psychiatry, we want To understand the entire benefit-risk profile of the drug. And So this was an opportunity to get to unblinded efficacy data in Exnova 2 a little bit more quickly, and that'll be in Q1 of next year. So when we unblind the data in Exnova 2, we have a well-powered efficacy phase 3 study. We'll have an understanding of the impact on the clinical scale of depression in anhedonia, and we'll be able to unblind and have a really good understanding ofthe safety profile as well. And in the meantime, we'll work to make some adjustments in terms of dose escalation across the program in psychiatry. I just want to be clear, there's absolutely no changes to the epilepsy program. But maybe I'll pause there because I'm sure there's a few things I've mentioned that you probably want to go a little deeper on. Yeah. And I guess we're also getting some investor questions and maybe the investor questions that we've gotten since the announcement too are, you know, basically if this is looking similar to what you're seeing in FOS, maybe why the pause in depression? And I think you hit on a couple of ways where you think you could probably just do better for this patient subset, but maybe can you talk a little bit about, these are discrete patient populations and probably are used to different AEs and maybe kind of what's more expected in an FOS patient versus an MDD patient. I guess anything on that, you know, might be helpful. Yeah, I think it's a really good question. We've had this conversation with a number of investors. I mean, just to be clear, these aren't new adverse events, right? And although the data are blinded data in psychiatry, you know, in looking at the data, we're very comfortable in saying these aren'T new adverse event for the mechanism and for the molecule. And we don't believe that there's any differences in the rates of these adverse events or the severity of these inverse events. So as I mentioned earlier, it really feels like the psychiatry program and the safety profile in psychiatry is looking more like the safety profile that's incredibly well understood in epilepsy. But then your question is, OK, if that was to be expected, then, you know, why did you why did you pause? And again, based on our phase two data, we actually saw something different. And so we were guided by our phase to data. And then as this profile emerged in phase three, that was the conversation with the DSMB. I mean, I think you hit the key point. These are different patient populations. In epilepsy, this safety profile, if you look at all of the epilepsy labels, and I know you've done a huge amount of work in epilepsy, both speaking with KOLs and prescribers, but also looking at the different drugs and the different mechanisms, we're very comfortable with the safety profile in FOS. And then as we go to depression, it's a different patient population. And our belief is we can make some adjustments to improve the tolerability profile, which would be important for that patient population, right? And then I guess, can you talk a little bit about next steps, sort of updates from the program? Will we hear about some of the, you know, program implementation steps to adjust maybe the dose titration or kind of will the next thing we hear from the the mdd side of things maybe be the q1 xnova2 data just kind of laying out the path forward for us sure so maybe let's talk about kind of that outside time point which would be q1 so in q1 we'll we'll have unblinded data so we'll be we'll be able to have a really robust conversation uh with you and with investors on what's the benefit risk once we've unblinded a large phase three clinical trial in major depressive disorder. Between now and then, we're going to be working on the dose escalation schema and what we believe is appropriate adjustments in the program. I will mention we have some data and information to inform that. And there's really kind of two pieces of information that I think are really valuable here. One is we've had a number of patients in the epilepsy program move from a double blind period to open label. You know, our open label rollover is incredibly high in the Epilepsy Studies. So we have patients that move from 15 milligrams up to 25 milligrams. So we get a good understanding that if you started as a lower dose and then went to a higher dose, what's the impact on the tolerability profile. We've also done a huge amount of clinical pharmacology work that is required to support the new drug application. And as some of those ClinPharm studies, we've also had dose escalation within those studies. So those data we haven't made publicly available, but we're very comfortable that in dose escalization that you can improve the tolerability profiling. So we've done a lot of work on that. And we've been able to do a lot which is actually a very common statement across CNS in general, right? Many, many drugs are titrated in these indications to help with tolerability. What's interesting about is that Ducalner is all of the doses we've tried in epilepsy and in depression are efficacious doses, right? They do separate from placebo. So we are actually starting in an efficacious dose and potentially moving up to a higher dose over time, which we believe will have an impact. So in terms of next steps, we need to do the work to determine exactly what that is. And then once we've made that decision, then we would update all of the regulatory documents, so protocols and other things that would be filed both with sites in terms of IRBs and going through sites approvals as well as regulatory approvals. So, you know, that'll take over the coming months to get through a lot of that work. So, practically, these things may converge in terms of the ExNova 2 data and all of the work we're doing to get ExNoVA 3 and the XSEED study up and running as well. But I think over the next number of months, we'll be able to provide continuous updates and kind of where we are in that decision-making process in getting these studies back up and running and obviously trying to get to the ExNOVA 2 data as quickly as possible as well." Perfect. And I want to make sure we hit on the epilepsy indications and pain. So maybe we'll move on to FOS and the filing. I guess maybe if you could touch a little bit about how many doses do you think physicians might be able to use in the real-world setting? Because as you mentioned, there's not necessarily a dose titration in the trial, but obviously in the real world setting, that might be a want, I guess, for KOLs. So if you could talk a little bit about that, and then we just get a few questions on kind of standard versus priorities, you know, so standard sort of the expectation for review, just given the number of agents that are out there or kind of how are you thinking about that? Sure. I'm happy to tackle the first one. Then Tucker, do you want to jump in on kind OF timelines and then how we expect that this would play out over the next little while. So yeah, I think your question is a really important one on doses and doses available. So we have filed on all four doses. So 10, 15, 20, and 25 milligrams. We've talked to the street about this for some time. And this was a discussion we had with the FDA, both at our end of phase two meeting, as well as our pre-NDA meeting. And we think that's really important. If you just think about how these patients are currently treated and how the prescribers use medications, the vast, vast majority of epilepsy drugs are titrated. So they're started at a non-efficacious dose and you titrate to tolerability and or efficacy and you make adjustments as necessary and often you're adjusting other background medications. One of the benefits of a Zetucalner is regardless of which dose you're starting on, whether it's 10, 15, 20, or 25, that is an efficacious dose. We have statistical significance at all of those doses in separation in terms of seizure reduction between the active dose and placebo. The general mantra for a lot of these prescribers is to start low and go slow. That's how they've been trained, and that's how they incorporate new medicines into their practice. With not having to titrate, not having to make adjustments for DDIs and a novel mechanism, we think this is going to be a very easy drug to prescribe. But given that background and how the epileptologists and general neurologists are trained in all of our market research, all of Our Advisory Boards, and I'm sure a lot of the discussions that you've had, is our expectation is that the starting dose in patients is going to be one of the lower doses and likely 15 milligrams. And I think that's really important. If you look at the 10 and 15 milligram doses of Azetucalner, they're almost indistinguishable with placebo when you look at the safety tables. A little bit more dizziness in the 15 milligram dose, but if you look almost, and you know we've published significant amounts of data on safety, all of those safety tables, you look across 10 milligrams which was used in XTOL or 15 milligrams that was used on XTol2, really it's tough to distinguish between that and placebo. So an incredibly well-tolerated dose and an efficacious dose and likely where patients will start. And then the prescriber in discussions with the patients will move appropriately depending on how much seizure control they're getting at the dose, what types of seizures they're having, and whether there's an opportunity to move higher. So I think it's really important we have four doses on label. So it gives patients a lot of opportunity to moving up and down as necessary. but we think likely the starting dose is going to be 15 milligrams, which is a really well-tolerated dose. Tucker? Yeah, to your second part of the question, Joe, look, we feel really good about the benefit-risk profile we have in epilepsy, and we've got the best placebo-adjusted MPC. We've got a novel mechanism and a drug that we think is going be really impactful for patients when we get it on the market. And though when you look at sort of standard versus priority, you know, it's a high bar, as you mentioned. There's a lot of ASMs out there approved today, So our expectation going in is that it's going to be a standard review, so 12 months from our filing here in September of 26. But we'll always advocate strongly for the drug. We think it's gonna be a really important addition to the treatment paradigm, and we'll do everything we can. But today, we think it said likely to be that kind of 12-month review cycle. Plus, in the back end, you know, most ASMs are scheduled, and so DEA scheduling is an additional three months post-NDA approval. And how should we think about sort of the initial launch cadence here? And is Xcopri kind of a good model? Obviously, that has a much more challenging titration and DDI profile, and azepticolor might be more applicable, or I guess received by, as we mentioned, the general neurologist. So I guess kind of how do you want to set expectations for what you can see out of the gate here? Yeah, I can take that. So look, we think ultimately this is going to be a really big drug, and as Ian said, one that's going to really work across both the epileptologist call point as well as the general neurologist. Whereas when you look at something like Xcopri, they're very much relegated to more of the specialists and the epileoptologists given their profile. So we think ultimately we've got a much larger opportunity that we can capture with a Zetra calendar. You know, we don't have a lot of data points in terms of ASM launches. Xcopi was the last one, as Ian said, back in 2019. And as you mentioned, there are challenges around that from the titration required to the down-dosing ASMs that launched during the pandemic. So we don't have a lot of good analogs, but we'll continue to do the work on the commercial side as our team puts together their go-to-market strategy and finishes off their pricing and demand work. So we didn't have any guidance for you today. I think ultimately, when you look back at prior ASM launches, there's a kind of narrative out there that's been low and slow. And it is a relatively conservative physician base across, but, you know, we think we've got opportunity with us at your calendar to do better than that, how much better we can bend that curve. You know, that's why I think what our team is really focused on. And as Ian mentioned, we've built now the kind of the core of our commercial team. We think we've got an excellent group that can help, you know, make this upshift good, but it's not going to be a rare disease launch, right? This isn't something where you're going to see a real spike and then a plateau. These are drugs that typically kind of are a little bit slower to launch, but always go to LOE and continue to grow. So, you Know, stay tuned for a little Bit more guidance qualitatively over the next, you know, nine to 12 months as we approach that NDA approval, hopefully this time next year. Perfect. And I wish we had another half an hour, but maybe in the last minute or two here, we could just touch on pain. Ian, you mentioned advancing some candidates into phase two. I guess maybe what did you see in the phase one experience that gave you the confidence to move that forward? And what will the investors see, I guess, in terms of data expectations at all from from this? Or is the phase two kind of the next big reveal here? So I think you're going to, we'll walk through the phase one data when the time's appropriate, which I think will be really informative and different for the two different programs. So NAV 1.7, I think is clearly an important target from a genetic point of view, right? The genetics associated with that are really, really strong, both on the loss of function and gain of function. And for 2025 years, pharma, including Xenon, has tried to drug this target, and it's been incredibly challenging. I think we have chemistries that have never been tested before. The profile of these chemistcies have never being tested before in humans. And I think that's a really, I think it's a we've had significant learnings. But really, the two key things that we want to learn from phase is one, are we getting enough receptor occupancy that we can mimic the human genetics to have an analgesic effect? And we believe we're there, which I think is really important. And then two, what is the safety profile? Because if you do inhibit the target very, very quickly, some previous drugs have seen some cardiovascular events, things like orthostasis and orthostatic hypotension. So we'll be looking at that as well. But again, I think these chemistries and what we know about them and the work that we've done in non-human primates as we've been ready to get into phase one is that we absolutely believe there's a therapeutic index and that we can dose high enough to get really good receptor occupancy and exposure to really try to run the experiment that the field has been trying to run for decades, which is if you can get good inhibition at the target with the right pharmaceutical profile, can you have an analgesic effect for this really high, high quality genetic target? So I think we are just in a leadership position there and really excited to get into phase two. On KV7, it's a little bit different. So KV6 doesn't have the genetic story associated with it, but the preclinical efficacy profile in pain models is very, very strong. And there was a previous potassium channel molecule called flupertine that had some strong pain data a number of decades ago. And so again, in phase one, we're really measuring, are we getting enough exposure in a human that we believe based on our preclinical data would predict an analgesic effect? And again, we've achieved that in phase 1. So yeah, I think there's going to be a little bit more data that we can share between now and initiation of phase 2. The nice thing about the phase 2 proof of concept studies in acute pain, we look at these post-surgical studies like bunionectomy or an abdominoplasty is those studies can move quite quickly and you can get to a readout quite quickly. Great. Awesome. Well, unfortunately, we're out of time, but thanks guys for joining us and thanks to all the investors for listening in today. Thank you, Joe. Appreciate it. Thanks, Joe!