Good morning. Welcome to the Xenon Pharmaceuticals Investor Webinar. Please note, this webcast is being recorded and broadcasted live on the investor section of Xenon's website. This broadcast is property of Xenon Pharmaceuticals, and recording, reproduction or transmission of this call without the expressed written consent of Xenon is strictly prohibited. All participants are in listen-only mode. You may submit a question in writing at any point during the presentation by using the chat form in the lower left quadrant of the webcast frame. I would now like to introduce Ian Mortimer, President and CEO of Xenon Pharmaceuticals, who will act as the moderator of today's event. Mr. Mortimer, you may go ahead. Thank you, operator, and good morning, everyone, and thanks for joining us today on our webinar. Apologies for starting a few minutes late. We just had a few technical issues that we were working through. But we will try to have the full 90 minutes, because we have a full agenda today. Before we begin, I'll point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to our SEC filings for additional details. We're pleased that you could join us today to discuss our XEN1101 program and the broader landscape in Major Depressive Disorder, or MDD. In addition to my colleagues, Dr. Chris Kenney, our Chief Medical Officer, and Dr. Chris von Seggern, our Chief Commercial Officer, I'm joined today by two preeminent leaders in the mood and anxiety disorder space, Dr. Sanjay Mathew and Dr. James Murrough. Dr. Sanjay Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Vice Chair for Research and a professor in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. He is also an active clinician. His research program focuses on experimental therapeutics and pathophysiology related to treatment-resistant mood and anxiety disorders, and PTSD, with a particular focus on rapid-acting and novel pharmacotherapies. Dr. James Murrough is Professor of Psychiatry and Neuroscience and Director of Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai. He is a faculty member of the Friedman Brain Institute and a primary principal investigator of the Center of Excellence in Neuropharmacology. Dr. Murrough conducts clinical and translational research aimed at understanding the biological basis of mood and anxiety disorders in order to point the way towards new, more effective treatments. For more details on their background and accomplishments, we have posted full biographies of our speakers on our website. Let me begin by providing a brief overview of the topics we intend to cover on the webinar today. First, Dr. Mathew will provide an overview of MDD, its treatment paradigm, and the current unmet need facing patients with MDD. Next, we've asked Dr. Murrough to provide some background on the Kv7 mechanism, along with an overview of preclinical and clinical work to date, supportive of the development of Kv7 channel modulators for mood disorders. This will be followed by an overview from Dr. Chris Kenney [will discuss] the clinical experience with XEN1101 to date, as well as the design of our phase 2 X-NOVA study in major depressive disorder. And finally, Chris von Seggern, our Chief Commercial Officer, will provide some background on the commercial opportunity for XEN1101 in the MDD space, based in part on our own market research with physicians. We will conclude the call with a panel discussion, addressing topics that were submitted both in advance as well as questions received during the webinar via chat. And I'm really excited to get this webinar kicked off with both Dr. Mathew and Dr. Murrough. Both of them have significant experience with this mechanism in MDD, both working clinically in the ezogabine work and also supporting a current study with XEN1101 in MDD, funded by the NIMH. So at this point, I'd like to turn the call over to Dr. Mathew. Over to you. Thank you very much, Ian, it's a pleasure to present on some of the unmet needs in this area for new therapeutics in depression. This is really a slide, a reminder to the audience that depression, as we think of it as the diagnosis, is extremely common and has a massive global burden. When you look and you compare the prevalence of depression compared to other psychiatric disorders, it's extremely common, and it tends to strike individuals during their most productive periods of life. The age of onset is generally in twenties, and it's very common in one's twenties and thirties, and that leads to great disability in terms of lost work productivity, absenteeism, and in some cases, suicide. It remains a major risk factor for suicide. Ten to fifteen percent of patients can go on to attempt suicide, and it's disabling in a number of ways. Besides mortality, it's really the lack of productivity. And the female preponderance is evidence. It's generally known to afflict females in a 2-to-1 ratio. Next slide. So when we think of the causes of depression and major depressive disorder, we have to really think broadly across brain circuitry... as opposed to a chemical imbalance idea. So the monoamine deficiency hypothesis has been the dominant hypothesis of depression really since the 1970s, with the idea that depression is linked to a dysregulation in norepinephrine, serotonin, and dopamine, the so-called monoamine systems. Over the last 20 years, we've really understood that depression is a problem in brain circuitry. So you see the brain circuit on the, in the right, diagram, and there are key nodes in the brain that subserve mood, and there's dysregulation in brain connectivity and excitability in broad neural networks, which may include the prefrontal cortex, amygdala, hippocampus, and then some of the brain reward systems, which Dr. Murrough will talk about, including Nucleus Accumbens and projections from Nucleus Accumbens. So the novel therapeutics in terms of pharmacology impact these circuits, impact the neurotransmitters within these circuits, and the neuropeptides within these circuits. In depression, we also have a number of neuromodulation treatments, including transcranial magnetic stimulation, deep brain stimulation, which is experimental, which target directly some of these circuits. So we've really rethought depression as much more than a simple imbalance of these monoamines, but really a broad circuit-based dysfunction. There are a number of risk factors for depression. There is certainly a genetic component, although it's been very difficult to isolate specific genes. It seems to have multiple genetic variants causing a susceptibility to depression. We know that early life trauma and traumatic and stressful events can lead to adult-onset depression. We know that substances of abuse, such as alcohol and other drugs, can lead to depression and raise the risk for depression later in life. There may be personality traits and other personality variables that pose a higher risk for a person to experience a depressive episode. The prognosis we know for depression can vary greatly among individuals, and although we have a relatively well-defined circuit of depression, we've not been able to translate that into a MRI or EEG biomarker that is definitively able to predict who's going to respond. So a challenge in our field is our treatments essentially are used in a trial-and-error fashion. So SSRIs may be tried, and we'll get to treatment algorithms, but they may be tried and hope that the patient succeeds without mapping it on to any specific change in circuitry or any predictors. And the prognosis can be quite poor, and the majority of patients, in fact, may not respond to the first available treatment in a satisfactory manner. Next slide. So as mentioned, it's highly prevalent, and in 2021, the diagnosis was found in approximately 21 million adults in the U.S. Many of them are treated with pharmacotherapies, and usually the pharmacotherapies are prescribed in the primary care setting. We know that 70%-80% of initial SSRI treatments are given by PCPs. Psychiatrists often only see the patient much later in the course of illness, could be, once the patient has failed two antidepressants. In addition to pharmacotherapy, there are psychotherapies as well as neuromodulation therapies. Anhedonia, which is, as you see in the list of symptoms, number two, is a markedly diminished interest or pleasure in almost all activities, nearly every day, most of the day. And it is considered to be a cardinal symptom of major depression, such that it's deemed to be so important for a major depressive episode that it's either depressed mood or anhedonia is required for the diagnosis, which is very interesting. You could actually qualify for a diagnosis of major depressive disorder and not endorse low mood or sadness. But if you have prominent anhedonia, that is sufficient for a diagnosis as long as you have some of these other associated symptoms, including changes in weight, changes in appetite, changes in what's called psychomotor agitation or retardation, fatigue, or loss of energy, feelings of worthlessness, excessive guilt, cognitive symptoms, and, and as mentioned, recurrent thoughts of death, which occurs in a proportion of patients. And these are the symptoms, according to the DSM-5, of a major depressive episode. Now, a challenge here is the heterogeneity, which we'll get to in the next slide. The clinical heterogeneity of depression is such that two patients can present in clinical practice with a diagnosis of MDD for DSM-5, but look completely different. One patient can present with hypersomnia, sleeping 12 hours a day, hyperphagia, eating excessively, gaining weight, lethargy, while another patient with the exact same diagnosis can sleep for three hours a night and have lost 10-15 pounds, have anorexia-type symptoms, and be agitated and highly anxious. That presents an immediate challenge in not only the diagnosis, but giving a treatment that will help such a heterogeneous condition. Anhedonia, or the loss of pleasure, is seen in the vast majority of patients. Some statistics suggest 70% will show clinically obvious features of anhedonia. We also know that anhedonia, loss of motivation, loss of interest, is something we see after patients may have experienced SSRI or SNRI treatments, such that they may have some residual symptoms. They're no longer complaining of depression, they're no longer complaining of anxiety, but they still lack the motivation to socialize, to engage fully at work and in their social lives, and so on. So that is a common residual symptom, which is a target for treatments, usually in the second, third, fourth line. And you can see here in this figure, the vast array of symptoms and the clinical heterogeneity, which often calls for augmentation strategies and other types of interventions where many patients are not getting into remission because of these residual symptoms. As will be discussed in a later presentation, we know that depression is associated with neurological disorders, such as epilepsy, 15%-50%, but also very commonly seen in MS, multiple sclerosis, seen commonly in stroke, traumatic brain injury, and so on. Next slide. The treatment paradigm in major depressive disorder. We know now for a number of years, the SSRIs are, which are generic medications at this point, are the first line, and that's because of the reasonable efficacy and relatively good tolerability when you compare them to the historical antecedents of the SSRIs up through the 1980s, which were the tricyclic antidepressants, which had the limitations of anticholinergic-type side effects, and lethality in overdose. SSRIs are much safer in that respect. Those are generally the first-line treatments. We generally start with generic escitalopram, generic sertraline, fluoxetine, et cetera. Second-line agents for those with partial response are then often switched either to an alternative SSRI or an SNRI, which may include venlafaxine, desvenlafaxine, duloxetine, and so on. And those are all generic as well. Or an NDRI, which is a norepinephrine dopamine reuptake inhibitor, namely bupropion, which is commonly used either as monotherapy or as a switch agent to after a failed SSRI. The STAR*D study was the largest effectiveness study ever done in major depression, and what it found is, after the first two lines of therapy, the remission rates go down enormously. So while the first two trials may result in remission rates in the 20% range, once you get to level three, remission rates can be on the order of 10%-15%. So it's a dramatic loss of effect if you give consecutive trials of patients with depression in real-world clinical settings. So what is third line? Third line often includes adjunctive atypical antipsychotic. There are several generic forms, including aripiprazole and quetiapine, and several branded agents, including REXULTI and... can't even remember the other one at this point. We'll get back to that. Third, fourth-line agents. VRAYLAR. VRAYLAR is the other agent, the antipsychotic. Third, fourth line would then also include monotherapy approaches of vilazodone, and then further down may include tricyclics, MAO inhibitors. And then once you get into refractory populations, fourth and later, you may be talking about Spravato, which is the intranasal spray of ketamine. It's so-called esketamine. Then other interventions may include lithium augmentation, tricyclics, then you could also consider electroconvulsive therapy or ECT, transcranial magnetic stimulation, and so on, once you get into fourth and later lines. So as you can see, there's multiple antidepressant options, more than 30 FDA-approved options at this point. But once you get into much later lines, the remission rates tend to be quite poor. Next slide. And so what is the primary drivers? In the absence of biomarkers or personalized medicine approaches, we used a joint decision-making approach with patients, looking at the side effect profile and often asking patients what are they willing to accept. So if a patient is not willing to accept the potential for sexual side effects, we may consider drugs such as bupropion earlier in the options. If a patient is really concerned about weight gain, for instance, we may go with certain choices as well. We talk to the patient in a shared decision-making approach based on generally the side effect profile, given the assumption that no one drug class is necessarily better than any other drug class when you think of first, second-line therapies. We also look at comorbidities. What else are patients suffering from? If they have a lot of insomnia, along with the depression, and their depression is getting better, we may be adding a hypnotic, such as zolpidem. We may add low-dose trazodone to assist with that. If there's a lot of comorbid anxiety, we may add either an atypical antipsychotic at low dose or a benzodiazepine. There's certain comorbidities where we may want to shy away from certain treatment options. So a patient with a history of addiction, substance use disorders, we may try to avoid ketamine, Esketamine, or benzodiazepines in those patients. Then, of course, patients with medical comorbidities, kidney or hepatic issues, we may be careful about drug-drug interactions in those patients. Then we also look at patients' histories. Are they at high suicide risk? That may make us want to avoid certainly tricyclic antidepressants. It may push us towards lithium augmentation, which has shown some benefit for suicide prevention. And then, again, we look at the overall risk-benefit profile based on the side effects of medications. Next slide. So then, to summarize the current unmet need, we are looking for novel mechanisms of action, rather than giving a patient a fourth, fifth trial of an SSRI or SNRI, which unfortunately is commonly done in clinical practice. We are interested in looking at new mechanisms of action, and we'll talk much more about that, and looking at patient subgroups, patients who have prominent anhedonia, who have prominent anxiety, who have other issues that are not being addressed with the current treatments. We know that efficacy can be a challenge. Few patients reach remission after certainly getting to a third trial. We look at the safety tolerability profile, and then one issue that we want to look at is the onset of action. We know drugs such as ketamine can work very quickly. There can be remission in some patients within several weeks, as opposed to 8, 12 weeks, as seen in SSRIs. And so one thing the field is looking at is, are agents that have perhaps more rapid onset of efficacy, as patients who are suffering for many months and even many years, often need a more rapid onset of efficacy to prevent hospitalization, prevent suicide attempts, and prevent morbidity. And I think that's the last slide of my section. Thank you. Great. Thanks. Yeah, thanks very much, Dr. Mathew. That was a very thorough overview of the MDD space and obviously the considerable need for new therapeutics. So we'll now turn the presentation over to Dr. Murrough, who will provide an overview of the Kv mechanism, the scientific rationale, and getting into some details of the clinical data generated with ezogabine and the work that Dr. Murrough and Dr. Mathew are doing with XEN1101. Over to you, James. Thank you, Ian. Great to be here. Pleasure to, as part of this webinar today. Next slide. So we started getting interested... I'm a psychiatrist, and truth be told, I had never heard of, Kv7 channels up until maybe five or six years ago. But I've learned a lot about them, since then, and as I'll explain in the next few slides, this really interest from a mood disorder and depression perspective in this specific channel, in this target, came out of a basic and translational research, in some of our, neuroscience labs that we collaborate. And many of you may already know this, certainly in the epilepsy space, but in general, potassium channels are coded by a very large family of different genes, and they serve to regulate membrane excitability, and generally, in general, they quiet down and reduce the chances of membrane firing. They sort of a function to repolarize the neuron after sodium channel activity triggers, for example, an action potential. So in this little diagram here, you see that after a neuron is fired, either burst firing or single action potential, potassium channels, and in particular here, a Kv channels, open to quiet it down. Just a quick word about nomenclature. Kv7 is synonymous. Also, you'll see in our work and others, they refer to as KCNQ. This is the nomenclature of the family of genes, the KCNQ genes that code for these proteins that form these receptors. And so you'll see me sometimes refer to this as KCNQ, and then there's five. And as you'll see, we've focused in on our interest in the Kv7.3, excuse me, two and three, which is also KCNQ two and three. Next slide. So there's a lot of data packed in here, but I'll try to explain. Really, I mean, maybe, honestly, they're more of a basic research. A few highlights pointed out in this slide. This is from going back, Eric Nestler's lab and many others. The field has used the various stress models to try to model behavioral and brain changes that might be relevant for depression. These are the preclinical models that many of you maybe are familiar with. This particular one, these research have utilized. It's called the chronic social defeat model, and I'll take you through kind of, very briefly. You basically have an experimental mouse, and you're interested in manipulating it through chronic stress exposure. In this particular form, the mouse is subjected to being co-housed with a mean bully mouse once a day for 10 days. That mouse that's been bullied will show a host of behavioral changes, some of which are reminiscent of depression, as well as anxiety and other things, and prominent what we might think of as anhedonia. One of the key behavioral readouts from the chronic social defeat is what we call the social interaction ratio. If you look at the, in the figures, the top left shows sort of an overhead view of this experimental setup, where you have the experimental mouse in the middle that's gone through the defeat procedure, and then you have a friendly target mouse that has a little smiley face there, and a healthy mouse, so affiliative, pro-social behavior, and spend a lot of time exploring and spending time in that interaction zone. A mouse that's gone through trauma, chronic stress, and is what we call defeated, will actually spend much less time interacting with that social mouse. You see the interact, the corner zones there, and that's a ratio. I'll show you some data, and basically, you can plot. For example, on the right, along the X axis interaction ratio. That's sort of the, the more time spent interacting with the target mouse, the, the better, the healthier. The punchline is, animals that go through this social defeat procedure actually show a divergent phenotype. They, about half, a little more than half, will show the avoidance, the social avoidance that I was just describing, that can be quantified behaviorally. They show a host of other changes. They show a tendency towards anxiety. Importantly, for this talk, and to link back to what Dr. Mathew was saying, they show reduced sensitivity to rewards, and that can be measured in a number of ways. A basic one that our colleagues have used is the sucrose preference test. A healthy mouse will, on average, prefer a slightly sweetened drink to water. But in the defeated mouse, they do not show that preference. So that could be taken as a very simple measure of anhedonia. So, that's the behavioral story, and that's shown in the top. And then in the middle row there, this gets into a little more about the electrophysiology. So it turns out, going back to some of these key reward systems that Dr. Mathew was talking about, in particular, focusing in on dopaminergic neurons projecting from the ventral tegmental area up to the nucleus accumbens, which we also refer to sometimes as the ventral striatum. This sort of represents the reward system, also involves the prefrontal cortex, but this is kind of the core, sort of limbic or mesolimbic reward system that focused on research in mood disorders, also relevant for things like addiction. It turns out that in the susceptible, depressed animals, and this is shown on the middle left bar graph, they show initially, unexpectedly, hyperactivity within the circuit. Now, you might think, well, if the animal's depressed, it should be low activity in the reward circuit. It turns out that the electrical profile of at least these dopamine D2-expressing neurons that project to the ventral striatum are abnormally elevated, and this has been replicated in a few labs. Other labs using different paradigms have shown other changes, but relatively consistent. It could be that ultimately, if there's a high background tonic activity, this system, which should be sensitive to registering change with rewards in the environment, is blunted in doing so. Ultimately, there's sort of less room to release dopamine in the forebrain to indicate a reinforcement. In any case, let's just take it for a second that you have this sort of hyperexcitability within this very specific circuit in rodents that tracks with depression versus you see on the gray bar, it says, "unsusceptible." That's the resilient or unsusceptible mouse, again, through just this divergent phenotype that emerges from this intervention. The higher the abnormal firing rate, the more the depressive behavior that's shown in the next two panels. And jumping to the punchline, why—how did sort of the Kv7 mechanism get on our radar is this is a—you see the table below. This is a very early. This was published in Cell in 2007, where the investigators simply asked the question, they said: What's changing in the brain? What's different between the resilient mice and the susceptible? Why, why are some mice in chronic stress? Why do they not show the depressive behavior? And long story short, one of the things is that animals that are—seem to be resistant to this show some type of inherent endogenous increase or upregulation in Kv7 channels. And in particular, we focused in on the 7.3, which is also the KCNQ three receptor. So this was a hint that the Kv7 protein is somehow involved in protecting animals from social defeat. Next slide. Fast-forwarding a subsequent publication in 2013 from the Han lab at Mount Sinai took this one step further, and they explored the ability of different types of manipulations after to either cause the pro-depressive phenotype, the anhedonic phenotype, or protect animals. So they did a viral vector overexpression and a host of things, but here I'm focusing in on their interest in trying to test whether pharmacologic manipulation of signaling at this receptor was relevant for the depressive behavior. And so, the procedure for these studies is you take the rodents, you put them through the social defeat paradigm, and then if they're resilient to stress, great. This set of experiments isolates those that actually show the depression, the, we'll go pro-depressive behaviors. Of course, it's not necessarily human depression, but we think it's likely relevant. The defeated, if you wish, the defeated, depressed mice are now subjected to... In this particular set of graphs, it's showing an eight-day schedule of an intraperitoneal injection of one of a variety of Kv7 modulators. They were interested in the drugs that may open the channel. The idea would be if you take an animal that's susceptible to stress, you give them a compound that could almost mimic an endogenous increase, right? Mimic an upregulation pharmacologically, that may represent a strategy to reverse this phenotype in rodents, and then that would need to be tested in humans. So this is the rodent work that sort of inspired us to do the human work. They used ezogabine, which is also known as retigabine in Europe, which is a first-generation Kv7 opener. What you're seeing in the graph on the top left is the behavioral reversal, as predicted, of treatment with the Kv7 opener. So the target, no target, that refers to remember, remember the little friendly mouse. So the set of bars on the left just indicate if the animals are treated with drug versus placebo, right, vehicle. There's no change in sort of overall locomotion. That's shown under the no target condition. But when there's a social mouse, which a healthy experimental mouse would want to investigate, hang out with, there you see a large increase, as predicted, what antidepressants might do in this simple model. And then as you move to the right, this is showing, as expected, a sort of normalization of hyper VTA neuronal excitability under conditions of retigabine. And then the bottom two just show other kind of commonly used behavioral endpoints in sort of the preclinical space for depression, including the forced swim test and the sucrose preference test, which I mentioned earlier. The forced swim test, these are little buckets of water, and the rodent will freeze or try to swim, and the more vigorously they swim, that's thought to be a reversal of the depressive phenotype. And in fact, that's what's shown under retigabine. Similarly, we see reversal of sucrose preference, all the way to the right under the KV7 opener condition. This was all very exciting to us and to condense many years of work into where we are. I'll tell you a little bit about some of trying to move this into humans. Next slide. This set up the-- this is, you know, I call it the KCNQ channel hypothesis of depression. Sort of, you know, to a reference to, to homage to, you know, what as psychiatrists, we all learned about the monoamine hypothesis of depression Dr. Mathew talked about. We know it's not the whole story. We're trying to look elsewhere, and this is one area that we've been investigating the last few years. The implication is that in some, at least, in some, some type of KV7 deficiency, at least within the reward system, and then targeting and enhancing that signaling could be a new mechanism to treat depression in general and perhaps anhedonia in particular. Next slide. This was the first double-blind study we did. We did a very early open pilot study where we just-- at that time, you could get ezogabine on the market. We-- our research pharmacy bought it. We treated a cohort of patients with depression. We saw improvements in symptoms, but that was a small study that led to our application and the funding by the NIH of still a very small by any standards, but 48 adults to do a double-blind, randomized study using ezogabine as kind of a tool compound. The point was, you know, we in academia tend to use a repurposing strategy where we want to test a novel mechanism, we use an available drug, and then we try to use biomarkers of things like target engagement. So in this study that was published several years ago now in the American Journal, the objective was actually to test the ability of, in this case, ezogabine, as sort of a representative of a class of drugs that was certainly new to us in psychiatry, that could actually increase the signal in the brain. That is one of our best signals that we can use in patient populations to look at brain response to reward. And in the interest of time, I won't go into the details, but we use functional MRI, and have individuals play a game where they could win, can model response in the brain to reward, and that was actually the primary outcome. We also measured a host of other things, not surprisingly, like anhedonia by self-report. So that's what's being shown here. This was a proof of concept mechanism study. If you know anything about Ezogabine, it's a long titration, takes four weeks to get to the target dose, and the goal of the study is that individuals were just on one week of the target dose, in this case, 900. That was sort of selected to be somewhere in the range that was shown to be efficacious for seizures. That was important to us, only did it meant it probably got into the-- which is a, a big issue, of course, in early phase, treatment studies. We weren't really looking for a clinical outcome, so we didn't think about classic eight weeks. We didn't necessarily think it was rapidly acting or not. We, we had no idea. It had never been studied before in this context. This was the design, four weeks to get to the target dose of 900, one week on drug, just to make sure all the biological effects at the circuit, at least the kind of acute effects, should be measured. They came in and had the outcome scan as well as the clinical data. Next slide. I mentioned the brain imaging findings. So just in the interest of time, we're not gonna go today. We did see a trend in the hypothesized direction of an increase being compared to placebo in brain. It was not statistically significant. So paper, again, for those details, Costi et al. in the American Journal. But what surprised us and surprised everybody was we saw quite robust clinical effects. And our sort of main depression scale is a commonly used matrix, and you-- that's what's depicted on the top right, and where we saw about a 7-8-point difference. And we did a number of measures of anhedonia. The SHAPS is a common one, the Snaith-Hamilton Pleasure Scale, and we used that and saw a similar profile. So this was alluded certainly exciting. It gave some initial plausibility to our hypothesis that targeting the Kv7 channel could be a novel approach to treat anhedonia and depression. Obviously, more work is needed. It should be noted, we found that the ezogabine drug overall was fairly well tolerated. This was sort of a general adult population with minimal comorbidity, minimal medical comorbidity, 18 to 65. I think about 95%—there was very little dropout. I think we had more than 90% retention. Again, small, short study, but very encouraging. Next slide. With all that, if you've been following, we applied to the NIH, and they wanted to fund a follow-up. They were also excited about this. The only problem was the drug we had used was not available to us anymore, and we were fortunate enough to get in contact with Xenon now many years ago. And they entered a collaboration with the universities to use their Kv7 compound to try to replicate and expand the data I just showed you in depression. This is going, and our target is to randomize 60 patients with 20 milligrams of XEN1101 or placebo under double-blind conditions. This is a two-site study with Mount Sinai and Baylor. And we're excited. And as Dr. Mathew said, the field is really for new ways to approach this disorder, so we're excited about the work. Next slide. I don't know if I have... I may have one more. Okay, just to wrap up. I think, yeah, we heard from the first talk, too, I-- that, that, that we need, you know, you heard that by the time you give patients a second or third antidepressant, you know, the results are disappointing. Insofar as they're mostly all working similarly, you know, that's thought to be one of the major problems. We don't really have a diverse armamentarium typically to reach for. You know, even if we don't necessarily have biomarkers yet to know which medicine to give which patient, at least to have greater options is something that clinically is very important that we're currently lacking. I reviewed very briefly some of the basic and translational research indicating that the KCNQ or, or Kv7 may be antidepressant, pro-resilient, anti-anhedonic. A lot of really interesting directions to go. And that's pretty much it. Great. Thanks, Dr. Murrough, and thanks for walking us through such a fascinating story on the early work done in some really important work preclinically and then moving into the clinical setting with the mechanism. So we really appreciate that overview. I'm now gonna pass over to Chris Kenney, who will summarize our clinical experience to date with XEN1101. Chris? Okay. Thank you, Ian. Good morning, everybody. Thanks for joining us. This slide right here, it covers a great deal of ground. It's talking about XEN1101 and all the work that's been done preclinically all the way through the clinic to date. Early on, XEN1101 was studied in multiple seizure models and was found to be robustly effective. And then as a follow-up, XEN1101 was also assessed in several models of depression, including the forced swim test, and then also the PRT, progressive ratio task, showing that there was indeed an antidepressant effect, at least in those preclinical models of XEN1101. And, of note, the concentrations that were used, the exposures in both rodent models, whether they were epilepsy or depression, were quite similar. So that, along with the typical sort of toxicology studies, laid the groundwork for phase 1 work. So the single ascending dose and multiple ascending dose studies were completed, showed favorable pharmacokinetics, which supported QD dosing, as opposed to ezogabine, which is three times per day. XEN1101, in this phase 1 study, was studied up to 30 milligrams, and the majority of adverse events were mild and CNS-related, as you might expect for a drug that crosses the blood-brain barrier. In phase 1, we also did a transcranial magnetic stimulation study, which showed that XEN1101 reduced cortical spinal excitability. There was a nice PK/PD relationship within that data. The effect was similar, but actually greater than that what was seen with Ezogabine. So taking the TMS study from Ezogabine, the TMS study from XEN1101, and coupling that with the safety and tolerability data from the phase 1 study, that laid the groundwork for phase 2b dose selection. So enter the X-TOLE Phase IIb study. XEN1101 in this Phase IIb study of over 300 patients showed a dose-dependent and highly statistically significant reduction in focal onset seizures and was well-tolerated. We have an ongoing analysis right now within the open-label extension of X-TOLE2, which shows that this efficacy signal has been maintained and actually improved over time, along with some interesting seizure freedom data as well. The adverse events that we're seeing in the open-label extension also are similar to what has been seen with other anti-seizure medications. So armed with phase 2b data, we had multiple regulatory interactions, including that with FDA and EMA, and this allowed us to come to an agreement on how to conduct our Phase III clinical trials. So we have two ongoing phase 3 studies in focal onset seizures, named X-TOLE2 and X-TOLE3, and we also have a primary generalized tonic-clonic seizure study ongoing in X-ACKT. So it's a fairly ambitious phase 3 epilepsy program. Switching gears from what Dr.Murrough. Was talking about with the investigator-initiated trial in depression to the Xenon-sponsored major depressive disorder trial, we call this study X-NOVA. That top-line data is expected in the next 2 or 3 months, specifically between late November and mid-December. So we're looking forward to sharing that information with you. Next slide. Okay, this is the study design for the X-TOLE Phase IIb study, again, in focal onset seizures. The screening period was followed by a baseline of 8 weeks, during which baseline seizure burden was assessed, and then those subjects who were eligible were randomized 2 to 1 to 1 to 2, either XEN1101 25 milligrams once daily, 20 milligrams once daily, 10 milligrams once daily, or placebo. So there were roughly 50 patients in the 20 and 10 milligram treatment arms, and over 100 in the 25 milligram and placebo arms. We're offering open-label extension for patients who complete the double blind. 96.5% of patients who completed the double blind opted for the open-label extension. That's a five-year study assessing 20 milligrams once daily in those patients. This data has been... The X-TOLE data itself, the double-blind data, was presented two years ago. The open label was presented at AES last year, AAN this year, and we're looking forward to updating the world on that ongoing data at the end of the calendar year at the American Epilepsy Society this year. So the X-TOLE data was really important in terms of helping us choose dose selection for X-NOVA, and this is the take-home message from the X-TOLE study from an efficacy standpoint. The primary endpoint in these studies is median percent change in monthly focal onset seizure frequency, so you want the seizure frequency to go down, obviously. So if you keep your eyes on the figure to the left, you can see that placebo had a reduction of 18.2% in the seizure frequency, while the high dose of 25 milligrams showed a 52.8% reduction, which was highly statistically significant. Then you can see the intermediate doses of 10 and 20 milligrams showed statistically significant benefits, but, numerically less so in intermediate between placebo and 25 milligrams. So a beautiful dose response. The figure to the right, which looks, very similar to the figure to the left, is really just making the point that the efficacy observed in the X-TOLE study, which was an eight-week double-blind period, was largely observed right off the bat within the first week. There was a placebo response, 25 mg responded better than the 10 and 20 mg, but most of the efficacy was already seen within the first week. We believe this is due to the fact that we're not titrating the drug. We haven't titrated XEN1101 in this phase 2b study. We're not titrating it in the phase 3 epilepsy program, nor did we titrate it in the MDD study, the, the Xenon-sponsored MDD study, which is in contrast to what Dr. Murrough was saying with the ezogabine proof of concept study, where four of the five weeks was spent in titration. Next slide. Depression's really important in people living with epilepsy. Dr. Mathew already relayed this number, but I think it's worth repeating, that the prevalence of depression in people living with epilepsy is somewhere between 15% and 50%. This is very common. It's the most common comorbidity. Greater severity of depression is associated with a higher seizure frequency. Depression is a strong predictor of quality of life. If you look at the figure to the right, you can see that the typical scale used for quality of life, the QOLIE-31, in epilepsy correlates with worsening depression. This depression in these epilepsy patients can actually predict a resistance to treatment, and also, unfortunately, tends to be a tendency towards less adherence to anti-seizure medications, which is obviously a risk for breakthrough seizures. So there's no doubt that, you know, most of the medications for epilepsy are mood neutral. Some of them can actually exacerbate mood. The potential to have something that could take care of both obviously would be helpful for these people living with epilepsy. Next. So you've seen this, the study design for the investigator-initiated trial from Dr. Mathew and Dr. Murrough, funded by the NIMH. This is the Xenon-sponsored phase II study in Major Depressive Disorder, which has a number of similarities. The study starts off with a screening period. Eligible patients are randomized one-to-one to one, either 20 milligrams once per day of XEN1101, 10 milligrams once per day of XEN1101, or placebo. This study was set out to randomize 150 subjects approximately. We went public and mentioned recently that we've randomized over 160. There's a safety follow-up of four weeks. The primary objective of this study is very similar to the data you've already seen, which is to assess depression using the MADRS over a 6-week period of time. That's the primary objective, and the secondary objective is to confirm or refute the evidence that Doctors Murrough and Mathew found that ezogabine improved anhedonia, as judged by the SHAPS scale. So that's our secondary objective. Number one, assess depression. Number two, assess anhedonia. I've already stated this once, but I think it's worth stating again that this data will come out either somewhere between late November and mid-December. So we're really looking forward to sharing this data with the world. And with that, I think that was my last slide. Thank you. Great. Thanks, Chris. Really good overview and a great transition from the trial design to Chris von Seggern and some of the primary market research and commercial work that we've done. Chris? Great. Thanks, Ian. So we've conducted a number of market research efforts that have helped us better understand the MDD treatment landscape, the nature of the disease, the patient flow, the burden of disease, and the unmet medical need, as well as seeking to understand how XEN1101 would fit into a future treatment paradigm, testing the potential product profile that's consistent with the, adverse event profile seen coming out of X-TOLE, but also, putting a perspective on what would be potentially the opportunity given different, profile attributes. Dr. Mathew did a great job, covering the landscape earlier in the presentation. So we'll primarily focus today on the right-hand side of this slide, really focusing on how physicians perceived the profile of XEN1101 in light of the attributes in a potential future environment. So reiterating a number of points that Dr. Mathew made, we've heard from our market research that there are several key unmet needs that create opportunity for future products in this space. The first and most important is physicians are clamoring for novel mechanisms of action. As Dr. Mathew pointed out, the majority of patients are exposed to SSRIs, not once, but twice, and perhaps perhaps three or four times through the course of their treatment paradigm. And as patients progress through treatment, physicians are actively looking for new mechanisms that can augment what has already been provided to patients, giving them a really a new or a different option, from what they've seen in the past. There are key components within the SSRIs, which do offer reasonable efficacy, but do have safety liabilities. It's something that physicians consistently point out as being part of the challenge of treating these patients, most specifically, sexual dysfunction as well as significant weight gain. As we've heard, there is interest from physicians in products that can deliver efficacy in a rapid period of time, given that the majority of these patients are focused on or have experienced long-standing disease by the time they progress through multiple SSRIs. We've heard through the course of this discussion that there are unique attributes and comorbidities within the MDD space that physicians are specifically focusing on, and anhedonia is one of those that comes up time and time again, particularly because, as Dr. Mathew mentioned, SSRIs don't often provide benefit along the dimensions of anhedonia. What we've shared with physicians is a profile, as I've mentioned, that is a product that has a novel mechanism of action. The Kv7 mechanism is quite interesting for physicians when they think about the context of the work that's been done from a preclinical perspective, as well as the Ezogabine data previously. Because of the unique potential to deliver a benefit along anhedonia, this is something that's viewed as a very important differentiator in the eyes of physicians. And as we've heard, the overwhelming majority of patients who experience major depressive disorder also have comorbid anhedonia. One of the unique components of the safety profile of XEN1101 is that there's been a lack of sexual dysfunction reported to date, and because so many patients choose to come off their SSRI because of this sexual dysfunction, clinicians view the lack of this, adverse event to be a real positive differentiator. What we hear, and this is very interesting from, physicians, is that efficacy in its own right is not the primary driver of treatment choice in this space. Obviously, products have to prove to be, efficacious, but what clinicians are really looking for are the top three attributes on this, on this page: a novel mechanism of action, one that treats unique components or, or comorbidities within the, disease, as well as, differentiated or, unique adverse event profiles that don't include significant weight gain or sexual dysfunction. It's within this context that we've heard very, very strong interest from physicians for using this product in later-line treatment therapies. In the context of this, what we see is that XEN1101 has a potential to play a really important role in the third line plus in this space. Again, in the context that the overwhelming majority of patients are going to see an SSRI or two or potentially three early in treatment, both because of physician comfort, again, long-standing use of these products over the course of several decades, as well as through payer management, with the expectation that patients are going to be exposed to at least a generic, perhaps two, before branded therapies come into the mix. But the compelling aspects of the XEN1101 profile are really important when physicians are thinking about transitioning into that branded space. And the profile that we've seen for XEN1101 to date suggests that it could be really compelling in that third line plus environment. So to summarize from the market research that's been conducted to date, first and foremost, the center of the value proposition for XEN1101, and what clinicians point to time and time again, is a novel mechanism that really offers an alternative to the mainstay of treatment today. With products that have been available for multiple decades, the Kv7 mechanism is really interesting, both from a scientific perspective, but emerging clinical data have pointed to the fact that it could offer a really unique alternative. Anhedonia rises to the level of importance when physicians think about the way to differentiate in this space. What we've heard is clinicians would be inclined to use a product that has specific benefit within the anhedonia comorbidity more frequently in that patient population. Again, it's one of the most frequent and hallmark components of the disease, but for those that do have documented anhedonia, it provides an opportunity to use this product perhaps earlier than they would when identified for patients who've passed through that first SSRI. What patients point... or what physicians point to in the course of our research is the lack of sexual dysfunction is a really compelling component of the side effect profile. When you think about this in the context of the overarching AE profile, what we did is we tested the AE profile to date seen with X-TOLE in the epilepsy population. It's the lack of sexual dysfunction that rises to the level of importance for what physicians point. All of the other ease-of-use attributes that are quite important in the focal onset seizure environment are equally important here. This is a QD product dosed at night with food, and physicians view that as an opportunity to perhaps dampen the impact of CNS-related AEs. As Chris Kenney mentioned, the product is being studied without titration and therefore has the potential to deliver early efficacy. Finally, the... To date, we've seen minimal to no TDIs, which when used in combination with other therapeutics, is a really compelling differentiator for XEN1101. Great. Thanks very much, Chris, and really nice to bookend the presentation where Dr. Mathew kind of walked through the medical need and then the work that we've done in our primary market research with physicians and the need for novel mechanism in treatment. So just briefly, I'm gonna provide a summary, and then we'll get into Q&A. So as we heard today from Dr. Mathew, MDD represents a large patient population, significant disease burden, and this despite the availability of numerous treatment options today. Novel mechanisms are needed desperately, and the most commonly used antidepressants usually, you know, are all from the same handful of class of mechanisms. We heard from Dr. Murrough that the preclinical and clinical studies to date with the Kv7 modulators, including ezogabine, may be beneficial for patients with depression and obviously the mechanistic connection to anhedonia. We have patient enrollment now complete in our phase 2 X-NOVA study in major depressive disorder. Topline data anticipated late November to mid-December of this year. And as you know, there's a second phase 2 clinical trial ongoing, which is funded by the NIMH with XEN1101 and MDD patients, led by Dr. Mathew and Dr. Murrough. And as Chris just mentioned, in our market research, physicians have really provided us some positive feedback on the potential profile of XEN1101. So that concludes the slides and the prepared remarks. We're now gonna move to Q&A. So, thanks so much for all of you that have submitted questions. Lots and lots have come in. We'll try to get to as many of them as we can. I will moderate the discussion, and in the remaining time, we are gonna go a few minutes past the top of the hour just because we did start a few minutes late. Thanks, operator, for putting the video screens of all of our presenters on, and we'll jump into Q&A. As we get into Q&A, I think maybe just starting big picture, and then there's some very detailed questions that have come in that we'll get to. But starting kind of big picture on mechanism... You know, obviously, we heard from both Dr. Mathew and Dr. Murrough, really kind of how the field has evolved over decades from the monoamine hypothesis to where we are today. And obviously, we continue to need diversity of mechanism and continued innovation. So it'd be really nice just to hear from the two of you. We'll start with Dr. Mathew, just on the need of novel mechanisms and kind of how the field has evolved and our thinking has evolved in treating these patients, over the time that you guys, the two of you, have been psychiatrists. Yeah. I'll start with that, and it's really been notable. I mean, really, for 20, 30 years, we've been wedded to one system, essentially, the monoamines. The atypical antipsychotics were different, but they're variants of the same theme, essentially, modulation of dopamine and serotonin. It was not until the ketamine story and the subsequent approval in 2019 of the esketamine nasal spray, did we really have a non-monoaminergic antidepressant. Since then, and over the last decade, there's been a host of research, not only in glutamate and GABA systems, and zuranolone is one of the examples of the GABAergic mechanism, but there's many other examples. With that, it's only been in the last few years, has there been really an explosion of research in the non-monoaminergic story. The most recent example is the combination of dextromethorphan plus bupropion, the so-called Auvelity, which was approved last year for MDD. So it's clearly, as the market research suggested, and as both of us see patients, this is what patients are asking for once they come to a psychiatrist. What's new out there? What can we sort of do beyond the standard fare? Dr. Murrough, to add, anything to add to that? Yeah. Just, I mean, I think Dr. Mathew covered it. I mean, I'm just thinking on the academic research side. I think we were talking about this before, you know, the NIMH. They often are reminding the research community that, "Hey, we've invested a lot in basic neuroscience, right, for mental health, including depression, mood disorders, over the past, let's say, two decades. And to date, we've seen very little payoff, right? Very little in the way of fundamentally new treatments for patients." So, the funding agencies that fund the majority of academic research in this space have also been growing impatient. It's worth saying. So, yeah, we're very excited, and I hope, you know, some of the advances that Dr. Mathew mentioned that hopefully this is-- we've reached some type of a tipping point, where now the knowledge base on how do these disorders work in the brain, right? We still don't fully understand. That's, that's part of the challenge. We have a fundamental challenge of bumping up against our limits in knowledge of, of brain function, right, as relevant to psychiatric disorders. Progress is being made. You know, every five or 10 years, we're told progress is being made, and the next wave of treatments is right around the corner, and we've-- most of the field has still been waiting for that. It's, and that's part of why we're so excited about this mechanism. Just to underscore, you know, we've talked a lot about the issue of your first line, second line. I mean, even you know, after a patient has had even a single good trial of a serotonergic or an SNRI, they're rightly asking their doctor, "What else you got?" Right? We're sort of constantly stuck in this more of the same, which likely, I think I mentioned earlier in the talk, we assume is contributing to that drop-off in responses because we're using the same, basically, quote, "the same, same drug." So just underscoring what was said before, I think th ere's a big opportunity. Mm-hmm. Yeah, I mean, obviously we completely agree in hearing that in our physician market research as well. So there's some detailed questions just on the ezogabine data. I mean, it's nice to have both of you. As I mentioned at the outset, you know, probably the two physicians that have the most experience in the world of this mechanism in MDD. Dr. Murrough, you walked us through the Costi study and provided- Yeah. us some of those data. But, Dr. Mathew, it'd be great to have your perspective as being involved in that work as well. Just an overall perspective on, the data that was generated in that placebo-controlled ezogabine study, and then I have some more detailed questions specifically about the work. Yeah. Well, I mean, I think the overall perspective, and which was somewhat of a surprise, was really the consistency of the findings. Now, of course, this was a small study with a biomarker endpoint, but not only was the MADRS positive, but really almost all of the secondary endpoints, including the SHAPS and a number of other scales that tap into anhedonia, as well as the self-report QIDS, which is the Quick Inventory of Depressive Symptomatology. Both the patient-reported outcomes and the clinician-reported outcomes were highly consistent with moderate to large effect sizes. That was really compelling, and, I mean, I think Dr. Murrough can attest that, I think we were surprised that- Yeah That it was consistently positive across PROs as well as the clinician outcomes. And it's not like the placebo response rate wasn't that suppressed. I mean, the placebo response rate in that study was 37%.... So, the drug response rate was 62%. So there was still a substantial effect size and a relatively low number needed to treat. So that really gave, I think, the mechanism a lot of confidence going forward. Great. No, I, I appreciate that perspective. So let's get, yeah, into some of the detailed questions that we're, we're getting. I know, I know it was mentioned in the remarks, but we, we continue to get questions just on the titration of Ezogabine, right? It takes... In that study, you titrated for four weeks. You used the 900- Yes ... kilogram dose, which we often talk about, as you know, the mid dose that was used for at least on the label, for treating focal onset seizures. And then you have that one week at the dose that the patients got to. So maybe just talk a little bit about, you know, the compare and contrast with 1101, that doesn't need to be titrated, and maybe your perspective on, you know, if the drug wasn't titrated or if the study was longer, kind of your expectations. Maybe Dr. Murrough, we can start with you. Sure. Yeah, sure. I guess this just underscores, you know, the surprise factor because it, you know, it's worth emphasizing that the Costi study that I presented was really a brain imaging study, even though I didn't show the brain data, because that's not really the point of what we were trying to talk about today. That's why... The thought was based on, you know, assumptions and precedent, you know, that in the context of looking at what are the at least acute effects of a putative antidepressant or some compound on neural circuitry in mood, we made the, again, somewhat arbitrary decision that we wanted at least a week on drug, on the target dose, make sure all the receptors are saturated, all the sort of at least sort of short to medium term, sort of one week, you know, 5- to 7-day, you know, homeostatic changes had a chance to occur. Because the readout is a functional readout of the circuit response to a psychological task, right? So otherwise, it doesn't make sense. It's way too short for an antidepressant trial. We spend all this time titrating. So that's the reason why it was designed as it was. If we could have started Ezogabine at the target dose, let's just say, right out of the gate, it probably would have been a one-week study. Now, who knows if that would have been time to see any behavioral signal, right? So maybe we got lucky. And the follow-on study we're doing with XEN1101 is meant to be able to pick up meaningful behavioral antidepressant anhedonic effects if they're there, which is why the new study is eight weeks. But I can tell you, the TID titration and all that, I mean, you know, the patients that participate in our studies, it's like, you know, God love them. I mean, they go through so much. There's a lot of hand-holding, and, you know, it's not ideal. I think the fact that we can do a once a day right out of the gate is a good thing, and we just kind of muddled through with the TID drug, and we got a signal, so you know. That's great. Dr. Mathew, you know, we had a question. You mentioned in your remarks earlier that we don't have any good biomarkers in, you know, in psychiatry and in depression, but, what's your perspective on, on maybe the fMRI and the incentive flanker test? Do you think that could be a biomarker? What's your perspective on that, at least as it relates to anhedonia and the reward circuitry? Well, I, I think it's a task that taps into that circuitry very well, from a research academic perspective. Now, I mean, it's never going to be a clinically applicable biomarker that a clinician would order an fMRI and use a specific task. Now, there may be specific situations in the future, I mean, as the field of TMS gets quite advanced and as, neuro navigation guided TMS, there will be certain centers and centers of excellence, and perhaps sort of interventional psychiatry centers, which will be very comfortable using fMRI and MRI in conjunction with therapeutics. But I, I don't think that task-based fMRI will sort of be a readily translatable thing for clinicians to use. Right now, we're very much using it as a proof of concept, mechanistic target engagement marker, as opposed to something that a clinician would readily adopt in their practice. Yeah. I'm going to bring Chris Kenney into the conversation. We get a lot of questions, which we did today, and we get them offline as well, just about the placebo rates. Dr. Mathew, you've talked a little bit today about it from COSTI. You know, Chris, maybe you can start on just reminding everyone what we're doing in the X-NOVA study to try to manage that as best we can, and then I'll pass it over to Dr. Murrough and Mathew to provide any perspective on placebo rates in these studies as well. Sure. Happy to, Ian. So it was really a multipronged approach to try to minimize the placebo effect in the X-NOVA study. So first of all, all of the sites, we have 20 sites. They're all in the, in the U.S., in the United States. That has historically been more favorable from a placebo perspective, as opposed to ex-U.S. We minimized the number of sites, but also, there's always a balancing between trying to get the recruitment done within a reasonable period of time, but we kept this number of site, total number of sites to a minimum. We don't have a huge imbalance in terms of one or two sites driving all of the recruitment. We chose a clinical research organization- That had experience within this therapeutic area. We were extremely diligent about the sites who were chosen, both in terms of the coordinators and, of course, the investigators as well. And then there's the patients, in order to get randomized, the last step is this: they have to pass the SAFER criteria. So there's an external review of each study subject to make sure that he or she really does have Major Depressive Disorder from a group that really has no skin in the game, so to speak, is just really trying to be as objective as possible. So there were a number of things that were done to minimize the placebo effect, and it's, you know, it's a challenge in this area, no doubt, so you got to do everything you can. Great. Thanks, Chris. Dr. Murrough, anything to add just on as a clinician in, as you think about placebo rate in these studies? Well, it's actually making me think the, the, question before about kind of the, what, what was it like going back, seeing some of the patients or hearing from the team in that Costi study? And I was reminded, you know, when you're in the context of a double-blind trial, right, it's - we knew people were getting better, but it's hard to get excited because there's the ever-present worry, what are they on, right? So you sort of. You try to, and this, you know, you train the staff, don't be too friendly with the patient, right? It's funny. It sounds so weird, right? And as a clinician, it's like, we think you do everything you can to make the patient feel better, right? You try to leverage any nonspecific factors you can. In the context of a randomized controlled trial, you're trying to not do all those things. You know, pep the patient up, right? If I'm a clinician, I'm prescribing, I say, "You're gonna get better," right? I don't say that with research participants. I say, "We don't know. Please tell us exactly how you feel." So just to underscore, it's a really very different way of interacting with participants because you still have to, they have to know you're a human being, and you care, and you're looking out for their safety. It's a really interesting, sort of, subtle thing that we don't talk that much about, but how to sort of manage expectations and try site by site, patient by patient, to isolate as much as possible a true signal while doing all of the things that it's important for these participants that are suffering from depression, right, by protocol. They're voting with their feet. They're here. They want to get better. They hope they get the medicine, right? So it's really interesting. But people were getting better, and I just like, "Man, I don't know which thing they're on," but, so anyways, just that's sort of the circling back to how do we think about placebo, just at least on a sort of patient-facing at the site level. It's always about sort of balancing and being supportive of participants while sort of stopping short of doing what we would naturally, instinctively do clinically, which is to sort of be their cheerleader and try to marshal any psychological or nonspecific effect we can to help them get out of their depression. Asking them about, "Are you getting your exercise in? Are you doing this?" We sort of try to not do that because we don't want to try to muddy up things. So it's just an interesting sort of position. Mm-hmm. That's helpful. As we, you know, again, the questions that are coming in, are also obviously placebo arm. We've talked about titration and the study, but really getting into some of the details of the data, and maybe over to you, Dr. Mathew. You know, when you think about the adverse event profile, obviously all drugs, we're thinking about benefit-risk trade-offs. We've heard throughout the presentation today some of the challenges with the existing antidepressants from an AE intolerability point of view. The Kv drugs, as we know from the ezogabine experience and the 1101 experience in both healthy volunteers, the work in epilepsy, and then the work that you've done in depression, is we do see, you know, depression, or sorry, we do see dizziness in a dose-dependent manner. We do see some somnolence of these drugs as well. Maybe you can just comment a little bit on the trade-off of adverse events and in your experience, at least with Ezogabine, some of the feedback on the safety and tolerability profile. Yeah. So, I mean, dizziness definitely appears to be dose-related effect, and patients generally did not drop out because of that effect. It was graded in the mild, moderate range for the vast majority of patients. So that's something we always look at: Is this a side effect, particularly if it's given at night, it's bedtime dosing, is this something that a patient can put up with enough since they're willing to continue with it? And by and large, that was the case with the Ezogabine experience. Same thing with somnolence sedation. So patients will vote with their feet in clinical trials, such they will drop out even after a week if it's intolerable and something they don't want to--can foresee themselves putting up with for the next 5-8 weeks. We very much look at the dropout rate due to the AE as a real, real, indicator. Yeah, that's helpful. Dr. Murrough, anything to add on kind of these trade-off of adverse events, depending on the mechanism and the class of drugs? Yeah, I mean, I think just maybe underscoring, thinking about if, you know, if there were a compound with this mechanism that is available as kind of a in the quiver for clinicians to reach for, and going back to what Dr. Mathew said about that shared decision-making. It's about sitting down with patients, seeing what they're willing to do, what they're willing to tolerate, and then trying it in a way that they feel involved. And we see a significant range of participants have strong feelings that I think I can tolerate this doc, but I refuse that. So it kind of just goes back to having talking about having different mechanisms, in part translates to having different side effect profiles that we can reach to, to match to patient preference. So it's less about something is more or less, but is there a variety? And again, just the data in the small Ezogabine study we did, I went back and looked. I think we had either no dropouts in the Ezogabine arm or very few, one or just a few, but there were several, I think four or five, that required some type of step down, and that's made from... They couldn't-- I think, like, two folks went from 900 to 750, and that was okay, and they hung on. One person went to 500, I guess, was the next. And so there was a smattering of that, but almost everybody stayed in. So yeah. That's great. Yeah, and consistent, I know with our, with our epilepsy work, is that not every patient is going to tolerate, the same dose, and so the ability- Right. To dose reduce is always important. If we focus a little bit more on the efficacy side, Dr. Mathew, obviously, maybe one of the advancements or the potential with this mechanism, and we've talked about it throughout this morning, is on anhedonia. Maybe you can just give your comments on the specific need around anhedonia that you see in the patients. Also, especially as these patients, at least in the clinical studies, are more on the moderate to severe side. Do you-- would you expect that all of these patients or a vast majority of them will have elevated anhedonia? And just maybe how those things track a little bit between a clinical scale of depression, like a MADRS or HAM-D17 and SHAPS. Yeah. Anhedonia can be a marker for severity in many ways. I mean, if you have a MADRS score in the 30s, 40s, you are going to endorse significant anhedonia hallmark. And anhedonia, ultimately, is a risk marker for poor function, can be related to suicide risk, and so on. It is a critical sort of subitem or dimension, however you want to call it. It's often what's... As I mentioned, it's something that's left over following first, second-line therapies with SSRIs. When it comes to a specialist, they're often, I mean, almost all of the patients we see have marked anhedonia. Patients, when they really are distressed, what they're looking for, they're not focused necessarily on reduction. They don't care about reductions in the MADRS, QIDS, and so on. They're looking at function. Am I, am I doing things? Am I engaged with my family? Am I present at work? All of these are markers of anhedonia, and so for them, it's probably the most critical aspect of the treatment. Thank you. Dr. Murrough, anything to add to that? Yeah, just maybe just from a kind of how we've thought about it from a translational research perspective. There's been a movement to try to, and in part, going back to what I said about trying to acknowledge the frank limitations we've had translating new knowledge in clinical neuroscience into new treatments for depression, and largely this goes across psychiatric disorders. But, part of the effort in the last five to 10 years to address it, that's been promoted by the NIMH that supports our work, is trying to break this heterogeneous disease down into the subcomponents, that the neuroscience knowledge will more closely match to a specific domain of illness, right? Going back to that slide that Dr. Mathew showed with all the circles. And to note, it is a syndrome, right? That's what we-- clinicians are often treating syndromes. It's not just in psychiatry. These things do hang together. Patients do walk in feeling anhedonic, having sleep disruptions, feeling worthless. Yet, this is a strategy, and we don't yet know if this will lead to more effective treatments for our patients. The strategy is break the diseases down into defined constructs, isolate the circuit, use translationally informed models and targeted compounds and other interventions to go after domains of depression. That's the whole-- that's the roadmap. In some ways, we were given, handed this roadmap by the NIMH and said, right? They've told us, "Don't, don't come to us and propose a new clinical trial for depression, please." Right? They've said, "We don't do that anymore. Let's, let's have a neuroscience-first approach. Let's isolate this. If you want to do a study of anxiety and fear responding to depression, fine. Anhedonia, okay, cognitive disturbance. But don't come to us and say you're going to study depression- Yeah. Because it's a heterogeneous syndrome, and kind of we've tried that, and it's, it's not working from their perspective." Again, going back, this maybe goes back seven or eight years. This is the so-called RDoC. An approach that the NIMH has talked and published on quite a bit. So this is our particular program of research that led us down this path, and our focus on anhedonia really was driven by RDoC, where we're sort of told, "No more MADRS scores, no more HAM-Ds. Pick something more specific and go for it." And so we picked anhedonia for all the reasons we've heard about today. Yeah. It's a cardinal symptom, it's key for functioning. We know quite a bit about its translational neurobiology. And we said, "All right, we'll, we'll try that. Yeah, that's some great background. Maybe I know we only have a few minutes left in terms of questions, but maybe we can just transition for a minute from depression, maybe into epilepsy. Starting Chris von Seggern, you know, we've had some questions that have come in just, you know, if this mechanism and specifically XEN1101 shows promise in the X-NOVA readout, and in the study that Dr. Mathew and Murrough are running, how that would, you know, kind of in our market research and in our interaction with epileptologists in terms of an anti-seizure medicine with mood benefit. Maybe you can talk about that a little bit from the feedback we've had. And then, Chris Kenney, there was a question on, you know, how are these patients that have epilepsy and comorbid depression, how are they treated, specifically the physicians involved in the treatment of those patients? So starting, Chris von Seggern, with you. Yeah. No, absolutely. So as Chris Kenney mentioned earlier, depression remains one of the most important and largest comorbidities within the epilepsy population. And it's something that in our research, we hear time and time again, that physicians are really struggling with from a disease management standpoint. It's important to note that the mainstay of treatment in epilepsy is Keppra for early line therapy, so levetiracetam is known to exacerbate mood-related disorders. And clinicians have said, from a market research perspective, that they are tailoring their treatments to move away for those patients with no mood or psychiatric-related issues, move away from levetiracetam early lines of therapy, moving on to, for instance, lamotrigine, earlier in the treatment paradigm than they would. And that builds the foundation for a really high level of enthusiasm for a product that both has a potent anti-seizure benefit, as well as potentially offering a benefit along depressive symptoms for those patients that have it. Again, when you focus on later line patients, as we've said, you end up with a rich, enriched patient population that is more likely to be difficult to treat, just in general from a seizure-related disorder. And there's really a high level of interest of a product that could offer benefit across both domains. Great. Thanks, Chris. Chris thoughts Yeah. You know, I'll start with some high-level comments and work my way down, keeping in mind that this is from the perspective of talking to epileptologists as a neurologist in the literature, so it'll be good to hear from our psychiatrists. You know, for these patients who ha- there's a lot of overlap between neurological conditions and psychiatric conditions. When the primary caretaker is the neurologist, he or she's gonna feel more comfortable with those issues than with the psychiatric, and vice versa if the primary issue is psychiatric. You know, by virtue of the way the training is done, at least in the U.S. and many other countries, it's done separately. You're either a neurologist or a psychiatrist. It can leave patients out, you know, in the breeze a little bit, unfortunately. So but as far as, like, treating these patients, I would say it's largely the same as you would treat a patient with major depressive disorder. Dr. Mathew already went through a focus on SSRIs, SNRIs, et cetera. I would just say that the neurologist is probably more likely to get uncomfortable if those medications are failing, and then ask for help from a colleague in psychiatry. And then I would say there's a couple other subtle comments as well. One, Wellbutrin or bupropion can lower the seizure threshold, and so you're gonna wanna avoid that medication. And then also, if you're dealing with an antidepressant that causes weight gain in a patient who's taking anti-seizure medications, which can also cause weight gain, perhaps you might wanna be a little more cautious about that. Yeah. So those are the sort of considerations that come to mind, at least from my perspective. That's helpful. Thanks, Chris. And we are, I think many people know in our phase III epilepsy program, we are looking at scales of depression. We're not stratifying for those patients, but we do expect to see some of, obviously, those patients based on everything we know in our phase III program. Okay, we're gonna wrap up here, but maybe final comments from Dr. Mathew and Dr. Murrough. You know, just anything else you'd love that you'd like to share with the group here, and maybe specifically, you know, on the KV mechanism, anything else that excites you in terms of your clinical research and where else we may be able to go? Just more broadly, in your field of expertise, what are the things that you think are really on the leading edge right now? Dr. Mathew, we can start with you and then move to Dr. Murrough. Yeah. I think one of the areas of interest we've touched upon is the issue of rapid onset of action. But there's been a lot of pushback on that, in that patients with depression, by and large, particularly when they're third line, have high rates of recurrence, and we view this essentially as a lifelong disorder. So the question, in many ways, becomes: What is the long-term prognosis, long-term tolerability, and what are the mechanisms in place that can support a patient's wellness, not one week after initiation, but one to two years later? That's something our field does not have enough data on. Most of the pharmacotherapies with the relapse prevention studies, they may go out 6 months, possibly a year. The vagus nerve stimulation studies have now gone out five years, which has provided a wealth of data for most ill patients. So that's the kind of data we need to generate more of. And so I was very intrigued, actually, that your epilepsy studies are doing five-year open-label extension studies, just something we never do in depression, and it's something our field needs to do a lot more of. Great. Thanks, Dr. Mathew. I appreciate that. Dr. Murrough? Yeah, maybe just ending with a thought that, you know, going back to kind of where the interest and excitement for us of this mechanism came was in this stress resilience model. I know I was sort of—it was sort of a rushed to go through, but that has broad implications. If we're talking about pharmacologically enhancing sort of endogenous mechanisms to increase resilience, which is really where this started. And if, if we know that chronic stress and different types of stress and trauma markedly increase individuals' risk for developing depression, that's why we use that as a model. But responses to stress are relevant to many, many disorders, of course. It's just intriguing that we started with a basic mechanism of asking a question: How, how, how do animals change their brain function to adapt to stress in a way that seems to protect them from these kind of classic maladaptive responses? A lot of implications there. Disease-wise, of course, thinking about things like stress disorders we deal with in psychiatry besides depression, like post-traumatic stress disorder, a whole world out there. You know, bipolar disorder, very difficult to treat, bipolar depression, very ineffective, compounds for that. I think there's a lot of ways. Also, if we end up believing in this sort of RDoC approach, focusing on anhedonia, and, is broadly seen across many disorders. In the future, we may think about medicines for these targeted, aspects like anhedonia, and start to get away a little bit. So a person could present with major depression, or anxiety disorder, or PTSD, or something else, or bipolar, or a neurological condition where they have anhedonia, reduced motivation, and a clinician in the future can think, "I can reach for a medicine for that." Again, these are the things that we've been pushed to, and that's why some of these studies, academic studies, have been designed as they are. So I think that's exciting, and it's a whole different way of thinking about treating CNS disorders. Yeah, that's a great way to wrap up. On behalf of everyone at Xenon, and Chris and Chris, Dr. Mathew, and Dr. Murrough, thanks for joining us today. A wide-ranging discussion. We covered a lot of topics. I know we weren't able to get to all of the Q&A, so we can absolutely follow up with people that still had outstanding questions, but really informative session, and we appreciate you taking the time with us. Operator, we can now end the call.