Xenon Pharmaceuticals Inc. (XENE) Earnings Call Transcript & Summary

Good morning, and welcome to the Xenon Pharmaceuticals Investor Webinar. Please note, this webcast is being recorded and broadcasted live on the Investors section of Xenon's website. This broadcast is property has been on pharmaceuticals and recording, reproduction or transmission of this call without the expressed written consent of Xenon is strictly prohibited. [Operator Instructions] I would now like to introduce Ian Mortimer, President and CEO of Xenon Pharmaceuticals, who will act as a 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. And 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. So we're pleased that you can 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 2 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. This 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 and 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 Freemont 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. So 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 Kv7channel modulators for mid disorders. This will be followed by an overview from Dr. Chris Kenney of the clinical experience with XEN1101 to date as well as the design of our Phase II X-NOVA study in major progressive 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 Levi 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, and it's a pleasure to present on some of the unmet needs in this area for new therapeutics in depression. And this is really a slide a reminder to the audience that depression as we think of it as the diagnosis is extremely common and it has a massive global burden. And 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 live. So the age of onset is generally in 20s, and it's very common in one 20s and 30s, 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. 10% to 15% of patients can go on to attempt suicide. And it's a disabling in a number of ways. Besides mortality, it's really the lack of productivity. And the female preponderance is evidenced, it's generally known to fix females in a 2:1 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 and balance 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 subsumed node 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 incumbents and projections from nucleosomes. 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 the susceptibility to depression. We know that early life trauma and traumatic and stressful events can lead to adult onset depression. We know that substances and the substances of abuse such as alcohol and other drugs can lead to depression and raise the risk for depression later in life. And 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 have not been able to translate that into an 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 will 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 center. We know that 70% to 80% of initial SSRI treatments are given by DCPs, psychiatrists often only see the patient much later in the course of illness could be once the patient has failed to 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 2 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 seemed 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 successive guilt, cognitive symptoms. And as mentioned, we current 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. So the clinical heterogeneity depression is such that 2 patients can present in clinical practice with the diagnosis of MDD for DSM-5 but look completely different. So 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 3 hours a night and have lost 10 to 15 pounds have anorexia type symptoms and be agitated and highly anxious. So that presents an immediate challenge in not only 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 treatment. Such that they may have some residual symptoms. They're no longer complaining of depression. They're no longer the planning 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. And as will be discussed in a later presentation, we know that depression is associated with neurological disorders such as epilepsy 15% to 50%, but also very commonly seen in MS, multiple sclerosis, seen commonly in stroke, traumatic brain injury and so on. Next slide. So the treatment paradigm in major depressive disorder, we know now for a number of years, the SSRIs with our 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 and overdose. SSRIs are much safer in that respect. So those are generally the first-line treatments. We generally start with generic citalopram, 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 in DRI, 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 2 lines of therapy, the remission rates go down enormously. So while the first 2 trials may result in remission rates in the 20% range. Once you get to Level 3, remission rates can be on the order of 10% to 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 this point. We'll get back to that. The third, fourth line agents VRAYLAR. VRAYLAR is the other [indiscernible]. 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 SPRVATO, which is the intranasal spray of ketamine, so-called esketamine and 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. So 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. So 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 have low-dose trazodone to assist with that. There's a lot of comorbid anxiety. We may add either [indiscernible] at low dose or benzodiazepine. And there are 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 ketamines as ketamine 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, the -- 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 that 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. And 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 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 session.

Great. 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 in getting into some details of the clinical data generated with ezogabine and the work that Dr. Murrough, Dr. Mathew doing with XEN1101. Over to you, James.

Thank you, Ian. Great to be here. Pleasure as part of this webinar today. Next slide. So we started getting interested on the psychiatrist and truth be told, I had never heard of KV7 channels up until maybe 5 or 6 years ago. But I've learned a lot about them since then, and as I'll explain in the next few slides, this really interests from a mood disorder and depression perspective in this specific channel and this target came out of a basic and translational research in some of our neuroscience labs that we collaborate. 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 in generally quiet. 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 first firing or single action potential potassium channels and in particular here, 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 I referred 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 5. And as you'll see, we've focused in on our interest in the KV7 3-- excuse me, 2 and 3, which is also KCNQ 2 and 3. 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 basic research. A few highlights point out in this slide. This is from going back Ericssons 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. So 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 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 bulling mouse once a day for 10 days. And then that mouse has 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. And so 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 terminal mouse in the middle that's gone through the bid defeat procedure. And then you have a friendly target mouse that has a little smiling face there and an affiliative pro social behavior and spend a lot of time exploring and spending time that interaction zone, a mouse that's gone through trauma, chronic stress and is what we call defeated. We'll actually spend much less time interacting with that social mount and you see the corner zones there. And that's a ratio. So I'll show you some data. And basically, you can plot. So for example, on the right along the tax interaction ratio. So that's sort of the more time spent interaction with the target mouse, the better, the healthier the punchline is animals that go through the social defeat procedure actually show a divergent phenotype. So they'll -- some of them, 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 is saying they show reduced sensitivity to rewards, and that can be measured in a number if one that our colleagues have used is the Sucrose preference test, a healthy mouse will tend to, 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 in 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 incumbents, which we also refer to sometimes as the eventful stride this sort of represents the reward system, also involves the prefinal cortex, but this is kind of the core sort of limbic or mesolimbic reward just only 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 is 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 [indiscernible] are abnormally elevated, and this has been replicated in a few labs, other labs using different paradigms have shown other changes, but to be relatively. 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 punted in doing so. So ultimately, there's sort of less room to release bitumen in the 4 brain to indicate a reinforcement. But in any case, let's just take it for a second that you have a 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 of phenotype that emerges from this intervention and the highly abnormal firing rate, the more the depressive behavior that's shown in the next 2 panels. And jumping to the pump line, how did sort of the Kv7 mechanism get on our radar is this is -- you see the table below. This is very early. This was published in Cell in 2007, where the investigator simply asked the question, they said, what's changing in the brain, what's different between the resilient mice and the susceptible? Why are some mice chronic stress? Why do they not show the depressive behavior. And long story or one of the things is that animals that are seeming 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 KCNQ3 receptor. So this was a hint that the KV7 protein is somehow involved in protecting animals from social. Next slide. Fast forwarding a subsequent publication in 2013 from the on lab at Mount Sinai, I took this one step further and they explore the ability of different types of manipulations after to either cause the prodepressive phenotype, the [indiscernible] or protect animals. So they did a viral vector over expression 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, but here, this set of experiments isolates those that actually show the depression of the pro depressive behaviors. Of course, it's not necessarily human depression, but we think it's likely relevant. So the defeated, if you wish, the defeated depressed mice are now subjected to -- in this particular set of graphs is showing an 8-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 like mimic an endogenous increase, right, mimic and upregulation pharmacologically, that may represent a strategy to reverse this phenotypic rodents and then that would need to be tested in humans. And that was -- so this is the road work that sort of inspired us to do the human work, they use ezogabine, which is also known as retigabine in Europe, which is a first-generation KV7 opener. And 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 we first to remember to remember the little friendly mouse. So the set of bars on the left, just indicate 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 VT [indiscernible] under conditions of retigabine. And then the bottom 2 just show other kind of commonly used behavioral endpoints in sort of the preclinical space for depression, including the for swim test and the Super preference test, which I mentioned earlier, the Force win 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 depressing 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. So this was all very exciting to us. And to condense many years of work to where we are. I'll tell you a little bit about some of trying to move this into humans. Next slide. So this set up, this is -- I call it the KCNQ Channel hypothesis of depression sort of to a reference to its homage to what a psychiatrist, 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 so this is one area that we've been investigating in the last few years. The implication is that in some -- in 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. So this was the first double-blind study we did. We had a very early open pilot study where we just, at that time, you could get ezogabine on the market. So 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 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 we -- in academia, we 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 with 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, is oven as sort of a representative of a class of drugs that were 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 a 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. And we also measured a host of other things not surprising as they like in terms of 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, it takes 4 weeks to get to the target dose and the gold the studies, the individuals were just on 1 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 a minute probably got into the which is a big issue, of course, in early phase treatment studies. But we weren't really looking for clinical outcome. So we didn't think about Classic 8 weeks. We didn't necessarily think it was rapidly acting or not. We had no idea never been studied before this context. But this was the design 4 weeks to get to the target gills of 900, 1 week on drug just to make sure all the biological effects at the circuit, at least the kind of acute effect should be measured, and then they came in and have the outcome scan as well as the clinical data. Next slide. The -- I mentioned the brain imaging finding is just the interest of time, we're not going to go today. We did see a trend in the hypothesized direction of an increase when compared to placebo in brain. It was not statistically significant terms of paper again for those details cost yet at all in the American Journal. But what surprised us and surprised everybody was we saw quite robust clinical effects. And our sort of main depression scales of commonly used matter is that's what's depicted on the top right and where we saw about a 7 to 8 point difference. And we did a number of measures of anhedonia. The shaft is a common one, the Snake Hamilton cycle scale, and we used that and saw a similar profile. So this has [indiscernible] 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 and minimal medical comorbidity, 18 to 65. And I think about 95% there was very little drop out. I think we had more than 90% retention. Again, small, short study, but very encouraging. Next slide. So with all that and if you've been following, and so we apply to the NIH and they wanted to fund the follow-up. They're also excited about this. The only problem was we didn't -- the drug we had used was not available to us anymore, and we were fortunate enough to get in contact seen on 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 and our target is to random patients with 20 milligrams of XEN1101 or placebo under double conditions. This is a 2-site study with Mosinee Baylor. And we're in. And as Dr. Mathew said, we're -- 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. So I think, yes, we heard from the first half to we need -- you heard that by the time you give patients a second or third anti-tip the results are disappointing. But insofar as they're mostly all working similarly, that's not to be one of the major problems. We don't really have a diverse [indiscernible] to reach for even if we don't necessary 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 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, 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 going to 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 covers a great deal of ground in fact 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 I work. So the single ascending dose and multiple ascending dose studies were completed showed favorable pharmacokinetics, which supported the QD dosing as opposed to ezogabine, which is 3x per day. XEN1101 in this Phase I 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 costs the blood brain barrier. In Phase 1, we also did a transcranial magnetic stimulation study, which showed that XEN1101 reduced corticospinal excitability. There was a nice PK/PD relationship within that data. The effect was similar but actually greater than that what we're seeing with ezogabine. And so taking the TMS study from ezogabine, the TMS study from XEN1101 and coupling that with the safety and tolerability data from the Phase I study that laid the groundwork for Phase IIb dose selection. So enter the XPO 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 XOL, 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 IIb 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 2 ongoing Phase III studies in focal onset seizures named XO2 and XO3. And we also have a primary generalized tonic-clonic seizure study ongoing in exact. So it's a fairly ambitious Phase III epilepsy program. Switching gears from the -- from what Dr. Murrough was talking about with the investigator-initiated trial in depression to the Xenon-sponsored major depressive disorder trial. We call the 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 XT 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 2, either XEN1101 or 25 milligrams once daily 20 milligrams once daily, 10 milligrams once daily or placebo. So there are 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 5-year study assessing 20 milligrams once daily in those patients. This data has been -- the XL data itself, the double-blind data was presented 2 years ago. The open label that was presented at AES last year, AAN this year, and we're looking forward to updating the world on the ongoing data at the end of the calendar year at the American Epilepsy Society this year. So the x tool data was really important in terms of helping us choose dose selection for X-NOVA. And this is the take-home message from the XTO 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% and 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 an 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, it's really just making the point that the efficacy observed in the XTO study, which was an 8-week double-blind period, was largely observed right off that within the first week. And so there was a placebo response, 25 milligrams responded better than the 10 and 20 milligrams. 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 IIb study. We're not titrating it in the Phase III epilepsy program nor did we titrate it in the MDD study the Xenon-sponsored MDD study, which is in contrast to what Dr. Murrough was saying with the ezogabine proof-of-concept study where they're 4 with 5 weeks was spent in titration. Next slide. So depression is really important and people living with epilepsy. Dr. Mathew already relayed this number, but I think it's worth repeating that the prevalence of depression and people living with epilepsy is somewhere between 15% and 50%. So this is very common. It's the most common comorbidity. Greater severity of depression is associated with 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 use for quality of life, the quality 31 in epilepsy correlates with worsening depression. And this depression in these epilepsy patients can actually predict a resistance to treatment. And also, unfortunately, has to be a tendency towards less adherence to antiseizure medications, which is obviously a risk for breakthrough seizures. So there's no doubt that most of the medications for epilepsy are moved 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 the study design for the investigator-initiated trial from Dr. Mathew and Dr. Murrough funded by the NIH. 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 1:1:1, either 20 milligrams once per day of XEN1101, 10 milligrams once per day of XTM1101 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 for 4 weeks. The primary objective of this study is very similar to the data you've already seen, which is to assess depression using the moders 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 shaft scale. So that's our secondary objective. Number one, assess depression, number to assess in anhedonia. I've already stated this once, but I think it's we're 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 segment and some of the primary market research and commercial work that we have. 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 potential product profile that's consistent with the adverse event profile seen coming out of XTO, but also putting a perspective on what would be potential the opportunity given different profile attributes. Dr. Matt did a great job covering the treatment landscape earlier in the presentation. So we'll primarily focus today on the right-hand side of the slide, really focusing on how physicians perceive the profile of XEN1101 in light of the attributes in a potential future environment. So reiterating the 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. And as Dr. Mathew pointed out, the majority of patients are exposed to SSRIs, not once but twice and perhaps 3 or 4 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 really a new or a different option from what they've seen in the past. There are key components in the SSRIs, which do offer reasonable efficacy, but you have safety liabilities 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. And then what -- as we've heard, there is interest from physicians in products that can deliver efficacy in around a period of time. Given that the majority of these patients are focused on rave experienced long-standing disease by the time they progress through multiple SSRIs. And we've heard through the course of this discussion that there are unique attributes and comorbidities within the FDD space. The 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 as a profile, as I 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 a major depressive disorder also have common anhedonia. One of the unique components of the safety profile of XEN1101 has then there's been a lack of sexual dysfunction reported to date. And because so many patients choose to come off their SSRI because of the 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 price is not the primary driver of treatment choice in the space. Obviously, products have to prove to be efficacious, but what clinicians are really looking for the top 3 attributes on this page, a novel mechanism of action, one that treats unique components or comorbidities within the disease as well as differentiated our unique adverse event profiles that don't include significant weight gain or sexual dysfunction. And it's within this context that we've heard very, very strong interest from physicians for using this product and we aligns reman 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 of the overwhelming majority of patients are going to see an SSRI or 2 or potentially 3 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 2 before random 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 being conducted today. First and foremost, the center of the value proposition for XEN1101. While clinicians point you time and time again is a novel mechanism that really offers an alternative to the mainstay treatment today. With products have been available for multiple decades. The Kv7 mechanism is really interesting, both from a scientific perspective, but emerging clinical data that pointed to the fact that it could offer a really unique alternative. The 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 me in anhedonia comorbidity more frequently in that patient population. Again, it's one of the most frequent and [indiscernible] 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 passed through that first SSRI. Well, 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 site office profile. And 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 XTO in the epilepsy population. It's the lack of sexual dysfunction that rises in the level of importance for what physicians point. And then all of the other ease-of-use attributes that are quite important in the focal-onset future environment are equally important here. This is a QD product dosed at night with food and physicians view that as an opportunity to perhaps the impact of CNS-related AEs. As Chris Kenney mentioned, there's the products being studied without titration and therefore, has the potential to deliver early efficacy. And then finally, the -- to date, we've seen minimal to no DIs, which when used in combination with other therapeutics is a really compelling differentiator for XEN1101.

Great. Thanks very much, Chris, and really nice to book end 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 going to 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 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 KB 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 II X-NOVA study in major compressive disorder, top line data anticipated late November to mid-December of this year. And if you know there's a second Phase II clinical trial ongoing, which is funded by the NIMH with XEN1101 in MDD patients led by Dr. Mathew, 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 in the prepared remarks. We're now going to 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 going to go a few minutes past the top of the hour just because we did start a few minutes late. So bank operator for putting the video screens of all of our presenters on, and we'll jump into Q&A. So 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. 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 2 of you, we'll start with Dr. Mathew just on the need of novel mechanisms and kind of see how our -- how the field has evolved and our thinking has evolved in treating these patients over the time that you -- the 2 of you have been psychiatrists.

Yes. So 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 [indiscernible] antipsychotics were different, but their variants of the same theme essentially, modulation of dopamine and serotonin. And 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. And so 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 GABA urgent mechanism, but there's many other examples. So with that, it's only been in the last few years as there's 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 valid, 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.

And Dr. Mora to add anything to add to that?

Yes. Just -- I mean, I think Dr. Mathew covered it. I mean, I'm just thinking on the academic research side, I think we're talking about this before, 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, 2 decades. And to date, we've seen very little payoff, right, but very little in the way of fundamentally new treatments for patients. So our -- the funding agencies that fund the majority of academic research in the space have also been growing inpatient it's worth saying. So yes, we're very excited, and I hope some of the advances that Dr. Mathew mentioned, and 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 part of the challenge. We have a fundamental challenge bumping up against our limits and knowledge of brain function, right, as relevant to psychiatric disorders, but progress is being made. And every 5 or 10 years, we're told progress is being made and the next wave of treatments is right around the corner. And we -- most of the field has still been waiting for that. So it's that's part of why we're so excited about this mechanism. And just to underscore, we've talked a lot about the issue of your first line, second line. I mean even after -- after a patient has had even a single good trial of the 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. Take we assume is contributing to that drop off in responses because we're using the same basically to the same drug. So just underscoring what we said before, but I think there's a big opportunity.

Yes, 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 [indiscernible] data. I mean if it have both of you, as I mentioned at the outset, probably the 2 physicians would have the most experience in the world of this mechanism in MDD. Dr. Murrough you walked us through the costly study and provided us some of those data. But Dr. Mathew, it would 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.

Yes. 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 is a -- 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 shafts and a number of other scales that tap into anhedonia as well as the self-report quits, which is the quick inventory depressive symptomatology. So both the patient reported outcomes and the clinician reported outcomes were highly consistent with moderate to large effects. So that was really compelling. And I mean I think Dr. Murrough can attest that I think we were surprised 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 appreciate that perspective. So let's get into some of the detailed questions that we're getting. I know it was mentioned in the remarks, but we continue to get questions just on the titration of ezogabine, right? It takes -- in that study, you titrate it for 4 weeks. You use the 900-milligram dose, which we often talk about as the mid dose that was used in for at least on the label for treating focal onset seizures and then you have that 1 week at the dose that the patients got to. So maybe just talk a little bit about the comparison XEN1101 that doesn't need to be titrated and maybe your perspective on if the drug wasn't titrated or if the study was longer, kind of your expectations? Maybe Dr. Murrough can proceed.

Yes, sure. And I guess this just underscores the surprise factor because it's worth emphasizing that the cost 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. Other -- that's why -- and the thought was based on assumptions and precedent that in the context of what are the at least acute effects of a putative antidepressant or some compound on neurocircuitry, in mood we made, 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 1 week, 5- to 7-day 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 spent 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 1-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 XEN1101 is meant to be able to pick up meaningful behavioral anti-depressant anti-anhedonic effects, if they're there, which is why the new study is 8 weeks. But I can tell you, the TID titration and all that, I mean, the patients that participate in our studies, it's like God love them. I mean they go through so much. There's a lot of handholding. And it's not ideal. I think the fact that we can do it 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.

That's great. Dr. Mathew, we had a question, you mentioned in your remarks earlier that we don't have any good biomarkers in psychiatry and in depression. But what's your perspective on maybe the FMRI and the incentive flanker test? Do you think that could be a biomarker? Or what's your perspective on that, at least as it relates to anhedonia and the reward circuitry.

Well, 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 neuronavigation 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 don't think that task-based FMRI will sort of be a readily translatable thing for clinicians to use. So 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.

Yes. 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 cost. Chris, maybe you can start on just reminding everyone how what we're doing in the X-NOVA study to try to manage that as a 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 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, where we kept this number of site total number of sites to a minimum. We don't have a huge imbalance in terms of 1 or 2 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, that last step is that they have the past to safer criteria. So there's an external review of each study subject to make sure that he or she really does have major protested disorder from a group that really has no skin in the game, so to speak, is just really trying to be as adjusted as possible. So there were a number of things that were done to minimize the placebo effect and 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 and as you think about placebo rate in these studies?

It's actually making me think the question before about kind of what was it like going back seeing some of the patients are hearing from the team in that cost study. And I was reminded 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 -- you train the staff don't be too friendly with the patient, right? It's funny. It's not 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. kept the patient up, right? If I'm a clinician prescribing at it, you're going to 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 they have to know your 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 is 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 what a they're on, but -- so anyway, just that sort of 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 tier leader and try to marshal any psychological or non sort of nonspecific effect we can to help them get out of their depression, asking them about are you getting your exercised -- are you doing this? We sort of try to not -- we sort of try to not do that because we don't want to try to muddy up things. So it's just -- it's an interesting sort of position.

That's helpful. And as we -- again, the questions that are coming in are also obviously, placebo array. We've talked about titration in the study, but really getting into some of the details of the data and maybe over to you, Dr. Mathew, when you think about the adverse event profile, obviously, all drugs are thinking about benefit-risk trade-offs. And we've heard throughout the presentation today some of the challenges with the existing antidepressants from an AE and tolerability 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 depression in -- or sorry, we you see dizziness in a dose-dependent manner. We do see some 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 the ezogabine some of the feedback on the safety and tolerability profile.

Yes. So I mean, dizziness definitely appears to be dose-related effect and patients generally did not drop out because of that effect. It was rated 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 net time dosing, is this something that a patient can put up with enough they're willing to continue with it. And by and large, that was the case with the ezogabine experience. Same thing with [indiscernible]. So patients will vote with their feet in clinical trials. Such a thing will drop out even after a week if it's intolerable and something they don't want to foresee themselves putting up with for the next 5 to 8 weeks. So we very much look at the dropout rate due to the AE as a row indicator.

That's helpful. Dr. Murrough, anything to add on kind of these trade-offs of adverse events depending on the mechanism and the class of drugs?

Yes. I mean I think just maybe underscoring thinking about if there were a compound with this mechanism that is available as kind of 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'll -- I can -- I think I can tolerate this stock, but I thought I refused that. So 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 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 is all about the study we did. I went back and looked, I think we had either no dropouts in the [indiscernible] arm or very few one or just a few, but there were several, I think, 4, 5 that required some type of step down, and that's the main from they couldn't -- I think like 2 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 everyone -- almost everybody that stayed in. So yes.

That's correct. And consistent, I know with our epilepsy work is that not every patient is going to tolerate the same dose, and so the ability 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 talked about it throughout this morning is on anhedonia. Maybe you can just kind of give your comments on the specific need around anhedonia that you see in the patients also, especially if these patients, at least in the clinical studies or more on the moderate to severe side, 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 D17 and shops.

Yes. So 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 a significant anhedonia very much. In anhedonia ultimately as a risk marker for core function can be related to suicide risk and so on. So it is a critical sort of sub item or dimension however you want to call it. And it's often what -- as I mentioned, it's something that's left over following first second-line therapies with SSRIs. So comes to a specialist, they are often -- I mean, almost all of the patients we see have marked anhedonia. And 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 quits and so on, they're looking at function. 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?

Yes. 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 5 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 clinicians are often treating syndromes. It's not just in psychiatry. These things do hang together, patients who walk in, feeling anhedonic, having sleep disruptions, feeling worthless. And yet, this is a strategy, and we don't yet know if it will end up. If this will lead to more effective treatments for our patients. But 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 road map. In some ways, we were given the hand of this road map by the NIH and said, right, that they've told us, don't come to us and propose a new clinical trial for depression, please. Right? They said, we don't do that anymore. Let's have a neuroscience first approach. Let's isolate this, if you want to do a study of anxiety and fear respondent and depression fine. Anhedonia, okay, cognitive disturbance, but don't come to us and say you're going to study depression because it's a heterogeneous syndrome and kind of we've tried that, and it's not working from their perspective. Again, going back, this maybe goes back 7 or 8 years, this is the so-called RDoC 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 really was driven by RDoC 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. It's a symptom. It's key for functioning. We know quite a bit about it's translational neurobiology. And we said, all right, we'll try that.

Yes, that's some great background. Maybe I know we only have a few minutes left in terms of questions. Maybe we can just transition for a minute from depression, maybe into epilepsy. Starting Chris Von Seggern we've had some questions that have come in just if this mechanism and specifically XEN1101 shows promise in the X-NOVA and in the study that Dr. Mathew and Murrough running, how that would 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's a question on 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 I'm starting with you?

Yes. No, absolutely. So 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 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 lines of therapy, moving on for instance lamotrigine earlier in the pardon they would. And that builds the foundation for a really high level of enthusiasm for a product at both has a potent antiseizure 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 an 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 a benefit across both domains.

Great. Thanks, Chris. Chris?

Yes. So I'll start with some high-level comments on down keeping in mind that this is from the perspective of talking to ability as a neurologist in the literature. So it will be good to hear from our psychiatrists. But for these patients who have -- there's a lot of [indiscernible] neurological conditions and psychiatric conditions. And when primary caretaker is a neurologist or she's going to feel more comfortable with those issues than with the psychiatric and vice versa if the [indiscernible] a psychiatric. And so by virtue of the way the training is done, at least in the U.S. and many other countries that's done separately or either or. And so it can lead patients out in the breeze a little bit unfortunately. But as far as like treating these patients, I would say it's largely the same as you retreat a patent with major depressive disorder. Dr. Mathew already went through a focus on SSRIs, SNRIs, et cetera. I would just say that the neurologist is 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 of other new comments as well. One well view gender can lower the seizure threshold, and so you're going to want to avoid that medication. And then also, if you're a press that causes weight gain and a patient who's taking antiseizure medications, which you can also cause waking perhaps you might want to be a little more cautious about that. 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 sales of depression. We're not stratifying for those patients, but we do expect to see some -- obviously, those patients based on everything we know in our Phase III program. Okay. We're going to wrap up here, but maybe final comments from Dr. Mathew and Dr. Murrough. Just anything else you'd love that you'd like to share with the group here. And maybe specifically on the KB mechanism, anything else that excites you in terms of your clinical research and where else we may be able to go? And then just more broadly in your field of expertise, what are the things that you think are really on the leading edge right now? So Dr. Mathew, we can start with you and then move to Dr. Murrough.

Yes. 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 their 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 1 week after initiation but 1 to 2 years later. And 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 Vegas nerve stimulation studies have now gone out 5 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 5-year open-label extension studies, just something we never do in depression. And it's something our field needs to do a lot more.

Great. Thanks, Dr. Mathew. I appreciate that. Dr. Murrough.

Yes. Maybe just ending with the thought that 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 have a sort of -- a rush 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 it has started. And if we know that chronic stress and different types of stress and trauma, markedly increased individuals risk for developing depression. That's why we use that as a model. But [indiscernible] to stress are relevant to many, many disorders, of course. And so it's just intriguing that we started with a basic mechanism I'm asking a question, 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. So a lot of implications there. Disease wise, of course, thinking about things like stress disorders we do with this psychiatrist besides depression like post-traumatic stress disorder. A whole world out there bipolar disorder, very difficult to treat bipolar depression, very ineffective compounds for that. So I think there's a lot of ways. And also if we end up believing in this sort of RDoC approach focusing on anhedonia and is broadly seen across many disorders. So 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 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, this is kind of -- 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. It's a whole different way of thinking about treating CNS disorders.

Yes. That's a great way to wrap up. And on behalf of everyone at Xenon and Chris and Chris. Dr. Mathew, 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 have outstanding questions, but really informative session, and we appreciate you taking the time with us. So operator, we can now end the call.