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

Welcome to the Xenon Pharmaceuticals Investor Webinar. This call is being webcast live on the Investors section of Xenon's website at xenon-pharma.com. This broadcast is property of Xenon Pharmaceuticals and recording, reproduction or transmission of this call without the express written consent of Xenon is strictly prohibited. Please note this call is being recorded. I would now like to introduce Ian Mortimer, President and CEO at Xenon Pharmaceuticals, who will act as a moderator of today's event. Ian?

Thanks, Jodi, and good morning, everyone. Thanks for joining us today on our webinar. Before we begin, I'll point out that we will be making some 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 consult the risk factors discussed in the press release from July 7 announcing this event and in our SEC filings for additional details. We are pleased that you could join us today for an in-depth discussion of our XEN1101 program and the broader focal epilepsy landscape in advance of our X-TOLE Phase IIb clinical trial results. We recently completed patient randomization of 326 patients, and we expect to release top line results in late September to mid-October. I'll act as the moderator for today's session. A few housekeeping items before we dive in. The first section of the event will be presentations by each of the speakers, and this will be followed by a Q&A session. [Operator Instructions] Your submitted questions will only be visible to myself as the moderator and to the other presenters. We have a lot of time at the end of the slide presentation to address as many of the questions as time permits. In addition to Simon Pimstone and Chris Von Seggern, my colleagues here at Xenon, I'm joined today by 2 preeminent epilepsy KOLs, Dr. Jacqueline French and Dr. Michael Rogawski, and they'll provide their perspectives on the adult focal epilepsy landscape as well as on XEN1101. I'll provide a more detailed introduction of the speakers when we get to their section in the presentation. You can access their detailed bios as available below the slide view. So let me begin by providing a brief overview of the topics that we intend to cover on the webinar today. First, Dr. French will provide an overview of focal onset seizures and the current treatment paradigm. She will touch on some of the factors influencing clinical decision-making and the current unmet need for focal epilepsy patients and where a novel antiseizure drugs, such as XEN1101, could fit into the treatment paradigm for these patients. Next, we've asked Dr. Rogawski to provide some background on Kv7 mechanism of 1101 and how XEN1101 as a next-generation Kv7 modulator differentiates from the first-generation Kv modulator ezogabine. This will be followed by an overview of the clinical development of XEN1101 to date and the ongoing Phase IIb X-TOLE clinical trial provided by Simon Pimstone, Xenon's Executive Chair of the Board. And finally, Chris Von Seggern, Xenon's Chief Commercial Officer, will provide some background on the commercial opportunity for XEN1101 based in part on primary market research that we recently completed with approximately 50 physicians. And after Chris' presentation, we'll conduct a panel discussion with all of our speakers as we address the questions we've received, and we're scheduled to wrap everything up by about noon Eastern time. So at this point, I'd like to briefly introduce the first speaker on our call. I expect many of you will be familiar with her outstanding leadership in the epilepsy space. Dr. Jacqueline French is the Professor of Neurology in the Comprehensive Epilepsy Center at NYU Langone School of Medicine and Founder/Director of the Epilepsy Study Consortium. She serves as the Chief Medical Innovation Officer of the Epilepsy Foundation and was past President of the American Epilepsy Society. Dr. French has been involved in a number of clinical trials for new epilepsy drugs. Her education, training, publication record and clinical experience make her ideally suited to comment on focal epilepsy, the medical need and where 1101 could fit into the treatment of adult focal epilepsy patients. And we're grateful that she can join us today. Dr. French, I'll turn the call over to you.

Thank you so much, and it's a pleasure to be here today to talk to you and talk to you about focal onset seizures, as we now call them. You may have learned at some point that these were partial seizures, but now we call them focal onset seizures because they start in one local area of the brain. As you can see here, we have just actually gone through a reorganization of the epilepsies by the International League Against Epilepsy. And now we actually subdivide epilepsy into 4 major categories: one of which is epilepsy which is purely generalized; another where epilepsy starts from one area of the brain or is focal; a third where both generalized and focal seizures occur, and these are people usually who have an epileptic and developmental encephalopathy; and finally, the group that we don't know where their seizures start, and therefore, at least for a period of time, they have to sit in a group of unknown onset. So focal onset seizures account for 60% of people with epilepsy. So it is the largest group. And as I mentioned, in this group, seizures occur due to abnormal neural activity in only 1 region or 2 -- if it's multifocal, it could be 2 or even 3 regions of the brain. And the consequences of the seizures may or may not lead to impaired awareness. They carry with them a very high risk of seizure recurrence, and seizures can result in lots of bad things occurring, including falls, trauma and sudden unexplained death. There are 3 major types of seizures that occur in focal onset epilepsy, and those occur depending on how far the epileptic activity spreads. If the seizure activity is contained within the small area where it begins, it may not have spread far enough to alter awareness in the individual. And you may have heard the term complex partial, simple partial. This would be -- this in the old parlance would have been a simple partial seizure. But now to make it more understandable to patients and to everybody else, we call it, the thing that it is, a focal-aware seizure. During that seizure, again, where the epileptic activity is contained to one small area of the brain, patients are awake or aware during the event, and they may be able to communicate. They often are able to communicate. They are able to hear and understand during the event. And often, that seizure will manifest as whatever the action of that little piece of brain is. So for example, if it's in the motor strip, it may involve a focal motor activity of a single extremity. If it's in the visual area of the brain, it might have flashing lights or even complex visual scenes, but all with the patient being able to see and remember what goes on around them. Focal-impaired awareness occurs when the seizure spreads far enough that it involves usually both sides of the brain and enough of the cortex that consciousness or awareness is impaired. The person is not on the floor. They are not unconscious usually. They are often still standing. They're still walking. They may be talking, but they are confused. They don't hear, understand, remember what's going on around them. This used to be called a complex partial seizure. Now again, to tell you more about what it actually is and make it more comprehensible, we have changed that name to focal impaired aware seizure or FIA seizure. And those can be extremely dangerous because people can wander during them. They can fall down in some circumstances. They can hurt themselves. They can put themselves in harm's way. And obviously, if they're driving, they would likely crash the vehicle that they were driving. And then the seizure type that is the most evolved and the most severe of the focal seizure types is the focal to bilateral tonic-clonic. That used to be called a secondarily generalized tonic-clonic seizure, and now we call it focal to bilateral tonic-clonic to distinguish it from a primary generalized tonic-clonic seizure. It starts in one side of the brain and then rapidly spreads to involve both deep brain structures and also the cortex. It is always associated with a fall to the ground or a loss of posture, stiffening of both sides of the body, the tonic phase; followed by jerking of both sides of the body, the clonic phase. And not only does the fall to the ground often cause injury, particularly if it happens on a hard surface, for example, but also we know that focal to bilateral tonic-clonic seizures confer other risks to people, including the most likely to be associated with a sudden unexplained death, which is one of the -- obviously, is the worst consequence of epilepsy. It also can be associated if multiple occur with cognitive deterioration over time. So we certainly are trying to control these focal to bilateral tonic-clonic seizures. So when we are presented with somebody and we diagnose them and we find out that they do indeed have focal epilepsy with focal onset seizures, we are going to try to treat them with the first antiseizure medicine. And by the way, I'm going to introduce you now to another new term. Rather than antiepileptic drug, we now call the class of drugs that treat epilepsy antiseizure medicines because we know that the majority of them, including the one we're talking about today, as far as we know, are symptomatic treatments. They don't actually treat the underlying disease. They treat the symptom of seizure, and some of them treat it very well. So we would start the first antiseizure medicine. Often, that would be levetiracetam or lamotrigine as very common first trials of antiseizure medicines. We choose that drug based on ones that we believe are safe, often ones that are easy to use by general neurologists and even primary care doctors are selected early on. And often, if the patient is easy to control, that first antiseizure medicine will be effective and will control seizures as long as it continues to be taken on a regular schedule. However, if that does not work and patients either are experiencing side effects or continue to experience seizures, they will switch to another monotherapy usually, although sometimes adjunctive therapy will be used. And ideally, the second medication would have a different mechanism of action than the first to increase the likelihood that, that would work if the first one had failed. If you are successful in either the first or second antiseizure medicine you were started on, then you fall into a category of easy-to-control seizures, easy-to-control epilepsy. And we think about 2/3 of people should fall into that category and do very well and maybe even eventually be able to get off of antiseizure medicine if their seizures are controlled. However, unfortunately, about 1/3 of patients fall into a second category, which is either difficult to control and severe -- maybe not severe but often difficult to control because 2 antiseizure medicines have not controlled the seizures. So the International League Against Epilepsy actually created a definition of treatment-resistant epilepsy and its failure of 2 adequately selected and used drugs to control seizures. So once you have failed 2 antiseizure medicines, the likelihood that other drugs, either alone or in combination, are going to control your seizures, unfortunately, is substantially lower. Often, polypharmacy is used in the difficult-to-control and often, these days, that might include 2, 3 or even 4 antiseizure medicines. Common medications used in this difficult-to-control group include VIMPAT, APTIOM, BRIVIACT and many more. And this is the group that would be considered for epilepsy surgery, devices, diets and other alternative therapies if medications are not working. Often, because you're combining drugs, there are increased issues related to safety and tolerability, and there is a significant cost, both a financial cost and an absolute cost to quality of life. These people have difficulty maintaining employment. They may even have difficulty finding a partner in life. They cannot drive. They often have to be under supervision in case that they have a seizure and their lives are very, very difficult. When you're looking at how many patients fall into these groups, the estimated U.S. diagnosed adult epilepsy population is about 3 million, of whom about 1.2 million have generalized or other types of epilepsy and about 1.8 million, as we said, about 60% have focal epilepsy. And if you think that about 1/3 of those will be difficult to control, that is about 0.6 million people. And then the worst of the worst who have very severe epilepsy that is frequent and really interferes with their life is considered to be about 0.3 million. Patients may initially respond to drug and may become treatment-resistant at any point in their journey, unfortunately. It is very much not uncommon for children to initially respond to drug and then when they reach their teens or early 20s to become refractory. And drug resistance may remit and reappear later on. So remission and return of seizures is unfortunately a common occurrence in people with epilepsy. So when you're looking at exposure to antiseizure medicines, about 50% to 60% will be easy to control with initial monotherapy and patients will be well managed. And then you get into the group of patients that are difficult to control and will often have to cycle through many antiseizure medicines. For example, patients who enroll in clinical trials, such as the trial of the Xenon drug, often have failed 10 or 12 or even 15 antiseizure medicines by the time they reach the trial. And so they really are cycling through drug after drug after drug. The 15% to 20% that are severely refractory are almost -- well, we hope that they are referred to academic centers for management. Unfortunately, that may not always be the case, but we really do suggest that they have a much higher likelihood of success if they are referred to academic medical centers. But they may typically remain uncontrolled despite, unfortunately, exhausting their -- both their pharmacological and non-pharmacological interventions. So although surgery is very successful in controlling refractory epilepsy, you have to be a candidate for surgery. And unfortunately, many people are not, and therefore, continue to experience severe treatment-resistant epilepsy. So what influences clinical decision-making? Certainly, as we discussed, the seizure profile and the burden to the patient, do they fall, do they wander, do they have focal to bilateral tonic-clonic seizures that are more dangerous to them? The higher the burden of focal to bilateral tonic-clonic seizures, the higher the likelihood of sudden unexplained death. The highest burden with patients with focal epilepsy who are experiencing frequent seizures, of sudden death is 1 in 1,000 per year, which means in a decade, their risk of sudden death may be up to 1 in 100, which is extremely high. We also worry about side effects and quality of life. We worry very much because even if you're having many seizures a day, that doesn't mean that you want to spend the rest of your time being sleepy, unsteady, having a poor mood. We also, again, are concerned about how easy it is for the patients to take the medication, whether there's a need for titration. Frequent dosing is very bad for the patient, particularly in a scenario -- as I said, these are symptomatic therapies, and they have to be taken as prescribed in order to have their action. And even missing a single pill can lead to dire consequences, status epilepticus in some people. And so the easier you can make it for people in terms of dosing, the better off you are. We also worry about the fact that this is a population that is very prone to what we call comorbidities, things that go along with the epilepsy probably because similar areas of the brain are impacted, including mood disorders; depression; bipolar disorder, which recently has been uncovered as a significant risk; anxiety; migraine. And we select therapies that we hope will not worsen these comorbidities, and in some cases, might improve them. So when we're looking at the key unmet needs for patients with focal onset seizures, the very first and most important thing, of course, is to have a more effective treatment for those who have not been able to find a treatment to date that controls their seizures. Significant portions of patients who progress on initial therapy are not well managed on polypharmacy and certainly could benefit from a drug that if it reduces their seizures, that's great; if it eliminates their seizures, that's even better. As I said, many people cycle through a dozen drugs. It's not unusual at all. If the drug happened to be actually beneficial in regards to some of the comorbidities, such as depression, anxiety or migraine, that would be a double plus because many of our medications that we use now actually make those comorbidities worse. And people are faced with a choice of having to live with some pretty nasty problems in order to get their seizures under control. But for many people, control of seizures is absolutely numero uno. We need drugs with novel mechanisms of action. We have a lot of sodium channel blockers out there. We want to work with rational polypharmacy. And in many cases, we prefer to combine different mechanisms of action. Often, combining, for example, 2 sodium channel blockers will lead to an exacerbation or pharmacodynamic enhancement of certain side effects, such as sleepiness, unsteadiness, double vision, et cetera. And we hope we can achieve a greater efficacy. And finally, we need -- we absolutely need drugs with improved safety and tolerability both for monotherapy and polytherapy. We don't want to compound the adverse events that people experience, such as fatigue, somnolence, irritability and cognitive impairment. As I said, some people have the concept that if you have treatment-resistant epilepsy, then you don't mind walking around dizzy and sleepy and tired. And that, in fact, is not the case. Obviously, you're going to probably take seizure freedom at any cost, but that doesn't mean that if there was an alternative, you wouldn't jump to it immediately. So what do we want from our new antiseizure medicines, which we absolutely need? We need a more effective treatment for difficult-to-treat patients, efficacy for our comorbidities, and we would like a novel mechanism of action. And the key characteristics that we're looking for is we want -- if it's comparable efficacy compared to existing antiseizure medicines, obviously, we would want a different group of people to respond because it's a new mechanism of action, or we would want better side effects. We would even take a drug with comparable efficacy and better side effects. So that brings us to the second one, which is we want a good adverse event profile that limits fatigue and somnolence, 2 things that people really do not like; irritability, again, something that people really do not like, and their families certainly don't like it. And some of our drugs that are most commonly used right now, such as levetiracetam, have a high risk of depression and irritability, and we need alternatives for that, something that can be started quickly with limited need for dose titration. Some of the drugs that we have take weeks to get to a target dose, and people may need a faster fix than that. At least a neutral impact on mood. Again, depression is a very common comorbidity in people with epilepsy. I already explained why single daily dosing is so important. You probably have heard that for other areas, there is sort of an 80% adherence that people would like to see, and then they say that you have good adherence. We're actually looking in epilepsy for 100% adherence. And try and do that with 2-time or 3-time daily dosing. It's extremely difficult. We would like to be able to address the comorbidities of depression, anxiety and migraine, and if possible, limited drug-drug interactions because people really -- there are so many antiseizure medicines out there right now that the ability of the average neurologist or a primary care doctor to remember all of the different drug-drug interactions out there, they really can't. So they need something simple. And we believe that that's why some of the more recent drugs are used so frequently, such as levetiracetam, because there's nothing difficult to remember. And as I said, a mechanism of action that's unique from existing antiseizure medicines. And so we get to XEN1101, which you're going to be hearing much more about. It has a Kv7 novel mechanism of action. Again, Dr. Rogawski is going to be talking about that. It is anticipated to have a strong tolerability and efficacy profile. And hopefully, it will turn out to be a novel broad-spectrum antiseizure medicine that will meet an unmet or many unmet needs in focal onset seizure. We already know for a fact that it can be dosed once a day and no titration is needed. So already, we've checked those 2 boxes. And it appears to have either a neutral or even a positive profile in regards to mood, which would offer a potential ancillary efficacy benefit. So thank you very much, and I will be happy to take questions later.

Great. Thanks so much, Dr. French, and that was an excellent overview of the adult focal epilepsy space and the considerable need for new therapeutics and what characteristics are important when we look at new antiseizure medicines. So we'll now turn the call over to Dr. Michael Rogawski, Professor in the Department of Neurology, with joint appointment in the Department of Pharmacology and an affiliate member of the Center for Neuroscience at the University of California Davis. Dr. Rogawski is an internationally recognized expert on drug discovery and development for epilepsy. His research encompasses laboratory studies as well as clinical trials in epilepsy. During his distinguished career, Dr. Rogawski has served on the Board of Directors of the American Epilepsy Society and as an adviser to the NIH and FDA and is the past President of the American Society for Experimental Neurotherapeutics. Given his significant research background, we're pleased that Dr. Rogawski could join us today to provide his perspective on the Kv7 mechanism and the importance for Kv modulation as it pertains to epilepsy. So Dr. Rogawski, we'll turn the call over to you. You're on mute, Mike, if you can unmute yourself.

Well, thank you very much, Ian, for that introduction, and good morning to all of you. It's a real pleasure to participate in this symposium. This slide summarizes some of the characteristics of XEN1101 that are salient. First of all, it is the only Kv7 potassium channel modulator in late-stage clinical development. It overcomes many of the limitations of a previous Kv7-targeted drug called ezogabine that I'll be talking about in some detail. This agent had a number of liabilities. It causes pigmentation abnormalities. There were urinary issues that we'll be talking about. And it has pharmacokinetics that required 3-times-a-day dosing. XEN1101 overcomes all of these concerns. It's not believed, as I'll discuss, to likely have pigmentation issues. It will be likely to be able to avoid the urinary symptom issues that plagued ezogabine. And the pharmacokinetics is such that it's suitable for once-a-day dosing rather than the 3-times-a-day dosing required for ezogabine. It checks the box in terms of novel mechanism of action that Dr. French spoke about. And I'll describe how this novel mechanism of action functions and why I'm so excited about the possibility of having an agent in the pharmacological armamentarium that acts by this mechanism. Ezogabine, the previous Kv7 modulator, is still FDA-approved, but it's no longer available to treat patients because the manufacturer removed it from the marketplace. So we don't have a drug currently that targets the Kv7 mechanism. Another aspect of the Kv7 modulator pharmacology that's recently become evident is the fact that drugs that target the Kv7 potassium channel may, in addition to the ability to treat epilepsy and also actually neuropathic pain was an area that was of interest during the history of the understanding of this mechanism. But it now seems that depression might also be a potential therapeutic opportunity for this mechanism. And many patients with epilepsy have a comorbidity of depression. So the possibility of having a drug that can benefit the patients, epilepsy as well as the depression, is very, very exciting for us in the field. Now I think most of you on the call are probably well aware of the fact that there are multiple antiseizure medicines available. We have upwards of 25 or even 30 different chemical entities that are currently approved globally to treat epilepsy. As Dr. French mentioned, some of these are sodium channel blockers. But we also have drugs that modulate the GABA system, either by acting directly on the GABA A receptor or by affecting the disposition of GABA at the synapse. We have one drug that is a blocker of a glutamate-mediated excitation. We have other drugs that work on various other targets, such as the SV2A synaptic vesicle protein, which is the target for levetiracetam and brivaracetam. The Alpha 2 delta protein is the target for gabapentin and pregabalin. And then for a number of the drugs, we don't really have a full understanding of the mechanism of action. For example, sodium valproate, a drug that's very important in epilepsy, we don't really understand its mechanism. But it's certainly clear that none of the presently available drugs, with the exception of ezogabine, which as I mentioned, is not currently available, target the Kv7 potassium channel. So the potassium channels are, of course, very important proteins that are involved in mediation of the neuronal excitability that's involved in information processing in every circuit in our brains. And they're an evolutionarily primitive ion channel. They're very diverse. They're more than 40 genes that encode subunits for voltage-activated potassium channels. The channels are what I referred to as heterotetramers, which means that they're made up of 4 subunits. And they basically act as pores in the neuronal membrane to allow the cation potassium, which is present in high concentrations in the internal milieu of the neuron from the inside to the outside are causing a hyperpolarization. And when the neuron is hyperpolarized that inhibits its activity. And so you can think of these potassium channels as being a neural break. So they inhibit the activity of neurons. And they -- Kv7 potassium channels are actually just a very small subset of the total number of potassium channels. I mentioned there are 40 subunits. These are organized into 12 different families. And the Kv7 family is, of course, just one of those families. It consists of 5 different subunits. The Kv7.1 subunit is present in the heart. And one of the positive aspects of XEN1101 is that it doesn't affect this cardiac channel. So it doesn't have cardiac side effects. It does, however, affect the Kv7.2 and 7.3 potassium channel, which is present in neurons. When these channels are mutated, they can actually lead to epilepsy condition called benign familial neonatal convulsions, and KCNQ encephalopathy are caused by mutations in these channels. And similarly, drugs that can activate these channels or open the channels can have an antiseizure effect. And of the numerous other potassium channels, it's only the Kv7 channels that seem to be suitable targets for an antiseizure mechanism. And the reason for that is that under normal conditions of the arresting potential of the neuron, when the neuron is hyperpolarized, the channels are not particularly active. However, as the neuron depolarizes, in response to an excitatory signal, the neuron moves toward the activation voltage for the Kv7 potassium channel. And so it essentially acts as a neural break and prevents the neuron from becoming hyperexcitable, essentially transitioning into an epileptic state. So the channels themselves are ordinarily antiseizure mechanisms in the neurons, in the neural circuit. And so basically, what drugs that enhance the activity of these channels do is they enhance the normal antiseizure mechanism of these channels. And they do this by shifting the voltage of activation to a slightly more hyperpolarized levels so that the channels are activated more strongly and can prevent the occurrence of seizures. The activation of this channel by this mechanism is predominantly going to affect the transition to an epileptic seizure. But unless the activation is very strong, it doesn't seem to cause significant side effects. Now the predecessor drug, ezogabine, unfortunately, had a very limited therapeutic range. The doses that were approved by the FDA were 200 to 400 milligrams, 3 times a day. And as you increase the dose, as seen on this slide, which was taken from the results of the pivotal trials that were submitted to the FDA for approval of ezogabine, you can see that there is some degree of dose-dependent increase in the therapeutic activity. That is in the median reduction in seizure frequency seen in the patients that were treated with these various doses. However, what was unfortunate with this product is that there's a substantial increase in adverse effects as you push the dose to try to achieve seizure freedom in patients that are treated with this medication. So even at this low dose, there's a significant liability for dizziness, somnolence and fatigue. And that really increases dramatically as you push the dose. So really, this drug is limited by side effects. I'll also mention this issue of the discoloration that was seen with ezogabine. When ezogabine was in clinical trials, it wasn't recognized that it could cause skin and retinal pigmentation abnormalities. But soon after it got onto the market and was made available to a large number of patients, people began to recognize that there was a bluish tint to the skin that occurred. And it turned out that there were also pigmentary abnormalities in the eyes as well. This caused a great deal of concern, of course. And the skin issues were largely of a cosmetic nature. But the FDA was particularly concerned about the possibility that the retinal pigmentation could cause serious problems because the appearance looked a lot like retinal dystrophy, which is associated with progressive development of blindness. There wasn't really ever any blindness or visual abnormalities that were of concern. But this caused the drug to be used very infrequently, and that is the reason why the sponsor decided to stop marketing it. The chemical structure of XEN1101 is somewhat similar to that of ezogabine, but you have a tertiary mean structure at the point where the dashed arrow is shown. And what that means is that there are carbon atoms at each one of those bonds on the nitrogen, which prevents the XEN1101 molecule from forming dimers that could lead to this bluish discoloration that occurred when ezogabine formed the dimers. So we don't think that there's going to be an issue here related to the formation of dimers and discoloration in patients who are taking XEN1101. Now XEN1101 is substantially more potent than ezogabine, or retigabine as the older name. In this experiment here, the plasma concentrations are being plotted against the inhibition of seizure activity. And you can see that XEN1101 is about 16x more potent than ezogabine in inhibiting seizures. But what's shown on the right-hand slide -- part of the slide, I think, is very instructive and helpful for us to understand how XEN1101 can be potentially much less fraught with the side effects that we spoke about in regard to ezogabine. And that is these darker bars indicate the potency of ezogabine in inhibiting seizures in a wide variety of animal seizure models that we use in the laboratory to identify a drug as a potential antiseizure agent in the clinic. And you can see that both of these agents have very broad spectrum activity in all of the various different types of models that we use. But importantly, ezogabine, the darker bars, is about as potent in all of the seizure models as it is in producing toxicity that we assess using the rotarod model. On the other hand, with XEN1101, you could see that the bars are much shorter, which means that they are -- this drug is much more potent in these models. And then the relative ratio with regard to toxicity in the rotarod is much greater. So the therapeutic window, at least in the animal models for XEN1101, is much greater than it is for ezogabine. And that suggests that it will be much better tolerated in the clinic than ezogabine. Another important development from the laboratory that Xenon has recently reported is the fact that XEN1101, from a pharmacodynamic sense, can be additive with a variety of medications that it would likely be used within the clinic, such as levetiracetam, valproate, lacosamide and the new drug XCOPRI, cenobamate. In all cases, in the animal seizure models, subtherapeutic doses of these -- of XEN1101, in combination with these other agents, resulted in a very good seizure protection, suggesting that these compounds can work well together. So I will just end with a summary then and point out that the Kv7 is a validated mechanism. We know that it's an effective antiseizure medicine from years of experience with ezogabine, as well as with the demonstration of broad spectrum activity in animal models for both ezogabine and XEN1101. The chemistry for XEN1101 is such that it's unlikely to form the dimer that is believed to lead to the significant issue of pigmentary discoloration of the skin and eyes. So we'll be able to avoid that. Also, there's a suggestion that we'll be able to avoid the urinary issues. I should have mentioned that ezogabine is about 85% excreted in the urine, so it reaches high levels in the urine, and that is believed to be the reason why patients experience the urinary issues. XEN1101 is metabolized in the liver and not highly excreted in the urine, so it can avoid those issues. XEN1101 has higher potency. It has the improved pharmacokinetics such that it can be used once a day. And so in summary, XEN1101 has many of the characteristics that we're looking for in a new agent to treat focal onset seizures.

Great. Thanks so much, Dr. Rogawski, and an excellent and comprehensive overview of Kv7 modulation and the improvements of 1101 over the first-generation Kv modulator, ezogabine. We'll now turn the call over to Simon. Most of you on this call know Dr. Simon Pimstone. Simon and I have worked closely together for the past 8 years. And this past June, he transitioned to his new role as Xenon's Executive Chair of the Board. And today, Simon will walk us through the clinical development of XEN1101 to date, and he'll also provide an overview of the Phase IIb X-TOLE clinical trial. So Simon, we'll turn the call over to you.

Many thanks, Ian, and thanks to all of you for joining today's KOL summary. I'm not going to spend a tremendous amount of time on the clinical. Many of you are quite familiar with our work to date. I think, obviously, the excitement is around our top line data in the X-TOLE study. But let me provide perhaps some context for that by just summarizing some of the key findings and trying to, in doing so, answer some of the questions that have been posed over time. A quick summary of the work to date. 1101 Phase I study was an adaptive integrated design, and very importantly, included a Phase Ib pharmacodynamic readout known as the transcranial magnetic stimulation or TMS study. I'll touch on that in a moment. Many of you are aware of that study, but it was extremely helpful in allowing us to select doses for the X-TOLE Phase II trial. Dr. Rogawski and Dr. French have commented on some of the potential attributes of 1101 that could be advantageous for this product. One of those, of course, is driven by the pharmacokinetic profile of the drug, which is very consistent with the once-a-day dosing. The drug is a long terminal elimination half-life. And the benefit of this, of course, particularly in one of the points Dr. French made, is in patients retaining compliance on these drugs is if they do miss a dose, breakthrough seizures generally can be quite a concern for these patients. In this particular drug, they miss dose the next day, for example, patients should have maintained trough levels to see them through and cover at least the predicted dose required for exposure. So we're very excited about this element of the drug's profile, is this once-a-day dosing but a long terminal elimination half-life, potentially allowing the prevention of breakthrough seizures in the setting of missed doses. Another important mention which has been made with this drug's profile is the lack of need of dose titration, which is obviously something that is quite common with other antiseizure medicines and indeed was similar with ezogabine. With 1101, it's different. We can start on the dose we end. And the drug reaches a near-steady state within about 7 days of dosing and is fully at steady state within a couple of weeks. Again, we think this is a very attractive profile as the dose escalates. We don't have long-term accumulation. We've done long-term nonclinical GLP tox studies out 6 to 9 months where, we do not see long-term accumulation of the drug. So this appears to be a very attractive element for the pharmacokinetics as well. Absorption is enhanced by food. This will be on the label. These are quite meaningful increase in exposure and bioavailability with food. Importantly, exposure increases dose proportionately and the 15- to 25-milligram daily dose in the fed state gives quite significant and important dose proportionality. Very, very useful is that there is rather low interindividual pharmacokinetic variability with repeat dosing. Of course, this can be a concern with any drug in terms of getting to desired exposure. Individuals often absorb drugs differently, metabolize, distribute and excrete them in a different way. With XEN1101, that interindividual PK variability is actually pretty low, which is very helpful in predicting at least exposure outcome in a treatment paradigm. The AE profile, we've heard a lot today already about what is going to be desirable. Of course, as with any CNS-acting drug, we would predict some CNS AEs, which are really driven by the mechanism of action, AEs like dizziness, sedation and blurred vision. But those, in our Phase I setting, were actually generally mild. We only had a couple of patients or subjects with moderate AEs or were reversible. None were serious. We've had no signal of urinary retention to date. This is an important point that Dr. Rogawski made. That certainly was evident with ezogabine. In fact, we've done bladder imaging studies in our Phase I multi-ascending dose arm, where we showed really no increase in post-void residual volume by ultrasound of the bladder after taking the drug. And as Dr. Rogawski has already mentioned, at least one of the components, we think, are clearly differentiated between this drug and ezogabine. It's not just that there is a degree of a modest degree of selectivity for the neuronal versus the bladder channels with XEN1101, but there really is very minimal renal excretion as well. The good news for us is we have not observed safety signals. This is cardiac or in safety labs, and no serious AEs either. So this is again a very important differentiation. Just to touch on our Phase Ib pharmacodynamic TMS study. This is a tool that can really study the effect of a drug on human cortical excitability and, to some degree, target engagement of CNS-acting drugs. I've said for some time, as we know from the cardiac literature, the Vaughan-Williams Classification allows us to predict the class of drugs' effect often by the way it acts on the cardiac action potential, the sodium or calcium or potassium channel-modulating agent or a beta-blocking modulating agent or beta-blocking agent may have certain effects on the cardiac action potential. And I think over time, as we study more selective CNS-acting drugs, we'll start to see a more predictable class effect using electrical signaling, such as EEG measurements in a TMS-like setting, and I think could be quite useful in actual predicting drug effect on targets. And multiple antiseizure meds have been shown to have an effect in the TMS model at their efficacious plasma levels. And of course, what got us interested in testing XEN1101 were some of the data published around ezogabine's use in a TMS model and particularly its effect on resting motor thresholds, which were measured using an EMG setting as shown on the left-hand side. The EMG assessment of pharmacodynamic assessment really allows one to detect activity of the drug, not just cortically but corticospinally, as you measure the force required to essentially induce a twitch at the thenar eminence, the thenar muscle. A drug that slows conduction will increase the force required to induce that same twitch. And what was observed with ezogabine was around a 2% increase in the resting motor threshold when using that drug in increasing the force required to induce that muscle twitch. Of course, EEGs are also used in a TMS setting. These are TMS-evoked EEG potentials known as TEPs, and they allow more direct evaluation of cortical rather than corticospinal excitability. But doing so also in a time-resolved fashion, as shown on the bottom one, can measure the effect of the EEG wave over time. And as I mentioned earlier, I think we'll start to see a more selective drugs that are similar in mechanism get tested. We may start to see a separation of mechanisms similar to what's observed in the cardiac action potential. Next slide. A real summary, I think, slide that maybe is the best take-home from our Phase I TMS data is shown here. What we're looking at in the green, over time, which is on the bottom X axis, is the increase in the resting motor thresholds observed with XEN1101 versus in blue, which is the placebo effect over time. And you can see not just a marked separation between the green and blue, the XEN1101 and placebo over time, but also a time-dependent increase in that resting motor threshold, reaching a maximum of 6 hours of around 4%. Now 2 important points to note. Number one is the red bar below, which is a concentration-dependent curve. So with a very strong PK/PD relationship in this particular study shown at 2, 4 and 6 hours, the PK and the PD effect are really mirrored. Another very important take-home here is that we only measured up to 6 hours. 6 hours was really the limit in the lab for technical reasons. These volunteers and staff couldn't stay overnight. And so we do predict that because the T max of the drug is seen at around 8 to 10 hours, it is likely that the maximal pharmacodynamic effect measured by resting motor threshold has not yet been achieved in this model. And we predict, as we do see higher exposures at 8 to 10 hours in subjects, we'll have an even higher resting motor threshold. Remember, the RMT observed or the change observed at the highest dose of ezogabine is around 2%, which is on the extreme left of this curve, effectively our 2-hour time point with XEN1101. So a very significant effect observed, a very strong correlation with plasma. And we don't believe we're at a maximum effect yet given these subjects were not dosed through to T max. Next slide, please. A question that gets commonly asked of us is how did we essentially dose-select for our clinical study. And what we've done here is we've shown our simulations for pharmacokinetic or PK levels and exposure levels of the range of those levels between min and max or peak and trough. For the different doses selected in the study, you can see the bottom curve reaching a steady state at around 2 to 3 weeks is your 10-milligram dose group. Your mid-curve is your 20-milligram, and your purple magenta curve is your 25-milligram predicted exposure range in the human subjects. What you're seeing with the dotted line shown across at around just under 60 nanograms per ml on the Y axis exposure is your EC50 data or exposure from the mouse MES assay and the DC model. And what you see in the highlighted box just below that are the plasma concentrations observed in the human subjects in our TMS study. Remember, these are concentrations between 2 and 6 hours where we're not at quite a concentration peak. But what you can see is the predicted simulation curve of 20 milligrams as the trough level that at 2 to 3 weeks is above both the highest exposure in the TMS as well as the EC50 in the mouse. And you can see our top dose 25 milligram achieving around a 30% higher maximal and minimal exposure versus the 20-milligram dose. And this really gave us good confidence for selection of that mid-dose of 20, with a lower and upper dose shown in this graph as well. Next slide, please. And so on the basis of that, we've now moved, as you know, through a Phase IIb trial we call the X-TOLE. This is a large subject setup with an 88% power in 300 subjects to detect a significance in the study. As Ian mentioned at the beginning, we've now completed randomization of 326 subjects, which will give us about 90% power, a very high power for a Phase II trial. As you know, there is a baseline screening and a baseline 8-week period, where subjects, importantly, have to get over certain 6 seizure thresholds. Eligible subjects are then randomized into 1 of 3 active arms and placebo. So it's a 4-arm study. But it's randomized as 2:1:1:2, 2 subjects in the high dose, 2 subjects in the placebo with 1 subject in the mid and low dose. There is a follow-up at 4 weeks for subjects that complete the double blind, unless they roll over into the open-label extension shown at the bottom, where they are then converted off to the double-blind, onto an active 20-milligram dose and followed for what was initially going to be a 12-month OLE, which is now at the request of a number of the investigators being extended to 36 months. As has been mentioned before, we believe the study has gone well. We had low dropout rates, lower than what was modeled. Of course, all of this data will be made available at a later time point with the data set, and also a very high open-label conversion, with above 95% conversion into the overly, which we were very excited by. End points. Standard primary end point is your median percent change from baseline in your monthly focal seizure frequency in 8-week double-blind treatment period compared to placebo. As I mentioned, the study is well powered. And one of the very important feature of the study is the electronic diary, which is being used to capture seizures. I think it's going to be very interesting to see how this pans out, but I do predict there'll be good adherence, and we hope those will allow for a cleaner data set as the e-diary is really much more of a real-time endpoint capture system. Next slide, please. Well, one of the features that we've talked a bit about today has been the potential for the Kv7 targets in mood disorders and some really interesting work from Dr. James Murrough at the Icahn School of Medicine at Mount Sinai, which has recently been published, looked in a controlled setting comparing ezogabine and placebo in patients with major depressive disorder and anhedonia. And this data is really summarized using the MADRS scale shown on the left, a marker of mood; and the SHAPS scale shown on the right, which is really a marker of anhedonia, with statistically significant and what is deemed highly clinically meaningful changes with improvements in the ezogabine treated on both in the MADRS scale on the left over placebo and in the SHAPS scale on the right over the placebo as well. And so on the basis of this data, where ezogabine has shown a potential benefit in mood in addition with some very exciting nonclinical data showing these particular Kv7 targets as potentially very interesting and important targets in anhedonia and major depressive disorder in animal models, we do anticipate initiating both an investigator-led Phase II proof-of-concept of XEN1101 for treatment of MDD and anhedonia. This will be run by Dr. Murrough from Mount Sinai, with colleagues at Baylor. But in parallel, Xenon is also planning, as many of you know, a company-sponsored clinical study of XEN1101, which will be run in parallel at different sites, a slightly different study design. So really just to summarize, and I'll hand over back to Ian in a moment. We've completed Phase I studies showing a promising drug profile with good tolerability. The TMS study has demonstrated a very strong PK/PD relationship and also a pretty pronounced effect on cortical and corticospinal excitation with XEN1101. We have now completed randomization in our X-TOLE trial. The Phase IIb readout is expected, as Ian has guided, late September, early October. And we now are also very interested and focused with this drug on major depressive disorder as a potentially very important comorbidity of focal onset seizures. And so hopefully, we see an effect in this condition. As was observed with ezogabine in prior Phase II studies, we believe this will be a very significant debt differentiator amongst other drugs for this disorder. Ian, I think that's it, and I'll hand over back to you.

Great. Thanks, Simon, and thanks for the review of the clinical data to date and also going through the trial design, the next steps for 1101 in X-TOLE. So the final speaker on today's webinar is Chris Von Seggern, Xenon's Chief Commercial Officer. Chris joined Xenon last year as our first CCO. Previously, Chris was a partner at Clearview Healthcare Partners, where he oversaw a number of commercial engagements as well as strategic due diligence on in-licensing and M&A. Chris has done an immense amount of work analyzing the commercial opportunity for XEN1101, both from primary and secondary market research sources, and he'll share some of those insights today. So Chris, over to you.

Thanks, Ian. And I have the pleasure today to share a bit of market research that we conducted to help inform our commercial perspective for 1101. Importantly, where we are at this stage, this research was focused on 2 components. One was to better understand the unmet medical need in the space. As we've already heard during today's discussion, given the plethora of options, one question we get frequently is whether or not there is a remaining unmet medical need in this space. And we wanted to characterize from a number of physicians their perspective on that key question. The second main component was to understand how the attributes of 1101 will help inform utilization of the product in the future marketplace. We still are waiting to test a true profile. So this discussion was much more focused on the elements of the profile itself compared to the existing products that are in the space. As is highlighted on the right-hand side of this slide, we conducted research in a blinded fashion with 50 clinicians, ranging from academic epileptologists to high-volume prescribing neurologists and epileptologists across the United States, with the goals of understanding how are they making their treatment decisions today, what unmet medical needs remain in the space and what are the attributes that would drive treatment decision-making for future anti-seizure medications in the future. A couple of the key takeaways that actually Dr. French highlighted in a very similar fashion earlier during her presentation is, first and foremost, there is a clear unmet medical need in this space. And we heard this from every single physician that we spoke with. From their perspective, while the first-line agents offer a benefit for a wide percentage of patients, there still are a very significant minority of patients that require multiple therapies in order to maintain or try to achieve seizure freedom. Because of this component of rational polypharmacy, what we heard again and again is the need for products that have improved safety and tolerability, alternative mechanism of actions to complement the first- or second-line therapies in order to try and increase the efficacy seen in these patients. This comes up time and time again from a selection perspective. Importantly, when you think about the range of comorbidities that are seen, we see this to be a big selection criteria as clinicians think about the second and the third, and sometimes the fourth and fifth agent, that are added to the treatment armamentarium. That's aside from the fact that there are subsegments in the patient population that have ingoing psychiatric comorbidities, migraine or pain that will inform different treatment selection options at the get-go. And this, again, informs what's a very messy and very complicated treatment algorithm that we'll touch on the next slide. When it comes to XEN1101, there's significant interest from clinicians in the attributes that the product offers. As we've already heard today, the novel mechanism is uniquely suited for addition into the therapeutic armamentarium. The safety and tolerability profile that's presumed to be positive is one that is very attractive in this space. And then the ease-of-use features that we consistently hear, QD dosing, no titration, make it easy to add this product into patients that require additional therapies to achieve additional efficacy. On the next slide, we highlight the treatment paradigm. And this is a quite complex and quite messy slide that I'll spend some time walking through. When you think about the patient population today, the vast majority of patients are exposed to levetiracetam as a first-line agent, and then from there, cascade through to other agents. And as you move down this slide, you're getting to an increasingly difficult-to-treat patient population as well as increasing polypharmacy to try and manage seizures. Levetiracetam is far and away the most commonly used agent, but it's not used for everyone. And in part the reason it's not used at the outset is for patients that have ingoing mood comorbidities. Frequently, lamotrigine is what we heard as the first-line agent for a patient that walks in with known depression or mood disorders as part of their clinical history. From there, you can see a wide range of next steps. The arrows on this slide represent the frequency with which we heard movement from one agent to another, either from monotherapy to monotherapy or in a combination environment. Moving down the list from levetiracetam. For those patients that experience a benefit from the product but have a mood component, typically wanting to stay in the class, you move from levetiracetam to BRIVIACT. For those patients that have mood issues, you can see a movement from levetiracetam to lamotrigine. As you move down for the rest of the agents, you can think about these as now being -- starting to become more of an add-on environment, adding VIMPAT, adding carbamazepine and then continuing to cascade down to alternative mechanisms of action when you run into efficacy-related issues. By no means is there a standard of care in this space. And as we've heard from Dr. French, there is a component of polypharmacy that is both rational, and in some sense, as irrational as you try to figure out each individual patient how to manage their seizure burden. On the left-hand side, clearly, seizure burden is what's driving use of these agents, but there are other components in terms of the age of onset, the degree to which there is existing -- preexisting or emerging mood-related issues. And then as you get down to treatment resistance, these patients tend to have a need to move on to more either potent agents as cenobamate offers or potentially going on to surgical options, as Dr. French mentioned. But importantly, many of the clinicians highlighted this concept of it's a trial and error. Each patient is a unique experience, and one needs to tweak and tinker the treatment paradigm in order to best suit that individual patient. And by no means, as a result, is there the standard of care that you can think about as being unique. But what we heard overarching across all of the clinicians is despite the fact that there are dozens of available products, there still are the need for additional products to be put into this treatment cascade giving -- given the fact that each patient is unique, and there are many patients that still remain without appropriate seizure management. As we think about the future, there are a few important components that will happen as XEN1101 continues in clinical development. The first is that lacosamide will lose exclusivity and likely move into one of the first or second lines of therapy. The product is widely used today. It's by far the leader, from a sales perspective, in this category, and clinicians do like the profile that it offers. And one of the restrictions -- or one of the limitations to even more widespread use is our market access consideration and some cost considerations for patients. So we anticipate, with a loss of exclusivity and the availability of generics, that lacosamide will move into what we are considering a first- or a second-line agent for those patients that offer or fall into that easier-to-control category. That being said, lacosamide does not deliver and none of these products deliver seizure freedom for the majority of patients. And we're in a situation where we imagine that the difficult-to-control patient population and the severe refractory patient population will likely remain unchanged in terms of total size. As a result, by the time XEN1101 enters the market, there still will be a meaningful number of patients that have residual unmet need that would benefit from an alternative mechanism of action. And we believe the attributes that we've spoken about today will inform treatment selection for XEN1101 for those patients that require a safe and tolerable agent that offers additional efficacy with a complementary mechanism of action. And again, this was something that was highlighted frequently by physicians wanting to stay outside of mechanisms that are used and the unique mechanism being something that is definitely of interest as patients progress through this polypharmacy environment. What's emerged as a result in the way we think about our profile in light of this clinical paradigm is that XEN1101 likely offers a really interesting and important treatment option for the future treatment paradigm. From the clinician's point of view, we heard this time and time again, we want safe and well-tolerated products. As Simon had mentioned, we saw lower-than-expected or lower-than-modeled dropout rates from the Phase IIb. We do not expect to exacerbate site comorbidities. And this is important because when combined with the potential to show a mood benefit, that would be differentiating for our product across the ASM category, where very few products, if any, are viewed to offer true clinical benefit within the mood disorder. At a minimum, showing no exacerbation of existing symptoms, again, offers differentiation for use in combination, for instance, with levetiracetam. Our evening dosing allows Cmax to occur while patients sleep. And this, from our perspective, will minimize the adverse effects that patients will experience while -- during their waking hours. And to date, we've seen no drug allergic reactions. When you move into the efficacy category, as we've talked about during today's discussion, this is a proven mechanism of action. We believe that we will offer broad efficacy as seen in multiple preclinical seizure models. And importantly, this mood benefit, as I've mentioned, is a differentiating feature that we hope to demonstrate with XEN1101. On the ease-of-use aspects, this is where we believe XEN1101 offers truly differentiating attributes. One pill once daily in this environment is quite unique. Combined with no titration makes us stand alone in this category. And those ease-of-use attributes are important because you have to imagine the patient that's receiving this product is experiencing continued seizures and is looking for an additional product to be added to the armamentarium that can potentially result in seizure freedom. Our unique mechanism of action and, to date, a low DDI profile makes us believe that we can be added in a rational polypharmacy environment for a wide range of patients, both with and without mood symptoms. And Simon mentioned this, and it can't be understated that the ability to miss a dose with this product is something that clinicians point to as being very favorable. While it's uncertain the belief system around what causes breakthrough seizures, when you talk to clinicians, they'll point to the fact that they believe their patients are not 100% compliant. Dr. French mentioned earlier, we're looking for 100% adherence and compliance, and any missed dose can result in a breakthrough seizure. And we believe the forgiving PK profile of XEN1101 enables us to, while not plan for missed doses, cover in the event that they do occur. And from a clinician point of view, this gives you a safe -- an ease of mind for a patient who you know is already suffering from seizures. And for a portion of those patients, they are likely to be due to poor compliance with their background therapy. So XEN1101 offers a good alternative for that patient who might be less than perfectly compliant, who needs an extra efficacy boost for -- to ensure that they don't experience breakthrough seizures. Each of these different components matters from a clinical decision-making. Not -- there isn't one category that will dominate decision-making for any one patient. As we mentioned before, there's a component of this which is tailoring and tinkering with your treatment algorithm in a per patient basis to get the ideal treatment algorithm for that patient. In some patients, safety and tolerability will dominate. In others, the need for additional efficacy, which is driving treatment change to begin with, will be the most important. For others, simply the ease of use is going to be what pushes the addition of XEN1101. And it's the combination of these 3 factors that we heard from the market research that makes this product such a compelling option within this future treatment paradigm. Ian, back to you.

Great. Thanks very much, Chris, and thanks to all of our speakers for providing important insights into the adult focal epilepsy space and also providing information on the opportunity for XEN1101 to play a meaningful role as a novel mechanism in the treatment for these patients. So to briefly summarize the highlights from today's session before we go into Q&A. FOS, or focal onset seizures, accounts for the majority of epilepsy patients. And despite many drugs being available, there still is a high unmet need and a need for drugs with novel mechanisms. Kv modulation is well validated for decreasing neuronal excitability, and 1101, to date, has shown pharmacy and preclinical potency and therapeutic index and, last, the ability to form dimers, clearly differentiating from the first-generation Kv modulator, ezogabine. And in clinical studies to date, XEN1101 has PK supporting convenient QD dosing and has demonstrated a strong PK/PD relationship. We're looking forward to our XEN1101 Phase IIb X-TOLE clinical trial results anticipated in late September to mid-October. And as Simon discussed, we have plans to initiate Phase II POC studies in major depressive disorder. And lastly, our commercial work that Chris walked through supports XEN1101 as a meaningful commercial opportunity and is a therapeutic option addressing a significant unmet medical need. XEN1101 has an only in-class mechanism, attractive ease-of-use attributes, and we look forward to our top line efficacy and safety and tolerability data available in the coming months. So at this point, I'd invite all of the presenters to turn on their videos. We've received many questions, so thanks for those, and we'll do our best to address as many of these topics as possible. If we don't get to your question, please feel free to reach out directly to the Xenon team and we'll arrange a time for a follow-up discussion. So I'm going to quarterback the discussion and direct questions to the specific presenters, and we'll all have an opportunity to provide additional commentary. So with that, let's start with the questions.

So we've had a number of questions that come back to the need in adult focal epilepsy. So for the KOLs, maybe can we discuss the need for new therapies. And related to this, a question we often get is there really seems to be a bifurcation of what have been very successful drugs in the treatment of FOS and then drugs that are much less successful. And so maybe you could provide a little bit of your perspective on what makes the drug in FOS very successful and those less so and the ongoing medical need. And Jackie, why don't we start with you?

It's a very good question, and it's not always what people expect. And it's not always something that you can anticipate from the clinical trial. So sometimes drugs have seemed to have very good efficacy in randomized controlled trials. I'll give the example of pregabalin, no drug interaction, no titration needed and then they flop in the clinic. And there might be some good reasons for that. In the case of that drug, I think that weight gain had a lot to do with it. Also, the efficacy, for whatever reason, just didn't seem to be as good in the clinic as it was in randomized controlled trials. I think that one good indicator that, that was going to be the case is that there were not very many people who were seizure-free in the randomized controlled trial. I think that a drug that maintains its efficacy, get some people seizure-free, is once-daily dose and doesn't cause comorbidities has a much better chance in the clinic than, for example, a drug that maybe has good efficacy but causes a lot of sleepiness, dizziness, unsteadiness, exacerbation of side effects such as irritability and depression. Those would have a much harder time. And Mike, maybe you want to weigh in.

No. I completely agree. And it's very difficult at this stage to predict how well a drug is going to be accepted. In the case of lacosamide, VIMPAT, we didn't really have anything early on to differentiate it. And then as it began to be used in everyday practice, it was something that people became aware of, and it grew in popularity. I think one point that I'll highlight is that the magnitude of effect that one sees in the Phase III clinical trials doesn't necessarily predict how well a drug is going to be accepted. Each patient, as you've heard, is different. And one patient may respond to a specific medicine, and then another patient may not respond. So we're very anxious to have more agents available so that we have an opportunity to benefit those patients who do respond, and we don't pay a lot of attention to the specific numerical values that one gets in the clinical trials. It's not something that really enters into the decision-making of a clinician.

I just want to add one more thing and that is, very famously, the FDA, way back when, Director once said that he didn't think that clinicians could actually tell whether drugs were any good or not. And that may be true of sort of maybe all clinicians writ large, but epileptologists are pretty good at figuring out relatively quickly which drugs are going to help their patients and which aren't. And I do find as a very positive sign, the enormous outcry to increase the duration of the long-term extension after this trial was completed as an indicator that -- because I have seen -- in my many years of doing this, I have seen many drugs were -- when the long-term extension was over, I was like, okay, that's okay. We're going to go on to something else, but that certainly was not the case here. There was a great desire to see patients continue to have access to this drug.

Thanks to both of you. We're getting a lot of questions that are coming in, digging a bit deeper into FOS. And so a couple of questions here that are related. But maybe upfront, Jackie, for you, are there any patient characteristics that you look for that will give you an idea if they're going to respond to a certain ASM?

Unfortunately, right now, we use actually patient characteristics to eliminate negative drugs rather than to say this person is more likely to respond. So if the drug makes you gain weight, then you don't want somebody who that's an issue for. If the drug makes you depressed, then you're not going to start it in a depressed person and so on. You certainly pick it on characteristics of this person needs a drug that they can take once a day because their adherence is not as good. But in terms of saying I think this mechanism of action will work for this particular person, unfortunately, it is really a black box as far as we're concerned.

All right. Yes. Go ahead, Mike.

I'll just say that from a research perspective, we're very interested to try to identify biomarkers that will predict antiseizure drug efficacy in any specific patient. But at the moment, that really doesn't exist. So it is largely a trial-and-error process. And I think that's one of the reasons why as clinicians, we're particularly interested in having this wide, broad spectrum of mechanisms available because we never know whether any specific drug is going to work in any specific patient. So for the difficult-to-treat patients, we cycle through many agents before we ultimately end up on the protocol for that specific patient. And so it takes time for the new drug to achieve its maximum impact in the space. But over time, the drugs do tend to be used broadly because we're searching for that group -- one agent or group of agents that's going to be effective for any individual patient.

Yes. Thanks, Mike. And we've had some questions that have come in specifically on transcranial magnetic stimulation, so I'll come back to that in a little bit to talk about kind of perspective on that as a potential biomarker or at least some kind of an indication for a pharmacodynamic effect. In still staying with kind of the treatment of patients and maybe, Chris, you can start on this one. We've had some questions on -- we know over the next couple of years, VIMPAT is going to go generic, but also BRIVIACT and APTIOM. And I know you've touched upon this and you've done a lot of the market research, but maybe you can start and then we can ask the KOLs to jump in also. But how do you think, if we think about 1101 launching into a number of these branded drugs moving -- those branded drugs moving generic, how do you think that's going to impact things?

Well, as I highlighted, VIMPAT and what we heard from the research, but VIMPAT likely will move up in line of therapy and be more broadly used. I think seeing that agent, which is one which has seen very steady growth across the category as clinicians become more and more comfortable and have exposure to the product. That product will likely be 1 of 3. But as I mentioned and what clinicians point out is a monotherapy. The product doesn't offer any better efficacy than any of the other products out there. So it's unlikely to change the nature of the patient population it's flowing through, but it most certainly will be used more. BRIVIACT and APTIOM are a little bit different in terms of what we heard from the clinicians. BRIVIACT is a product that clinicians favor if they saw positive experience in levetiracetam, but likely will not be moved up into that first line of therapy, again, with the availability of levetiracetam, which is used much more frequently. From a comfort standpoint, we didn't hear that product moving up into that first line, and again, likely will be in that bucket of products that patients experience in a second and third line. And the same concept is with APTIOM. So from a size of the patient population, clinicians didn't expect to see a dwindling patient population in later lines of therapy because so much churn is occurring, but certainly moving VIMPAT up into 1 of 3 environment is something that we would expect to see.

And Ian, just to highlight, VIMPAT is a drug that acts on sodium channels. So it's fundamentally similar to carbamazepine, oxcarbazepine and other sodium channel blockers that Dr. French mentioned are common in practice. And so it doesn't really offer a differentiated mechanism. And similarly, brivaracetam is a second-generation levetiracetam. They both act on the SV2A target and doesn't offer a differentiated mechanism either.

Thanks, Mike.

I'd just add one more thing, and that is, actually, a characteristic we haven't really talked about a lot yet, which is spectrum of activity. And Mike said in his talk about -- or discussed the fact that retigabine and the Xenon compound were broadly effective across different animal models. We don't know yet, of course, whether that's going to translate into -- when I talked originally about the fact that there's generalized epilepsy, focal epilepsy, many neurologists are rather simple people, and they want one drug for all. And if there is some question about whether somebody has focal epilepsy or generalized epilepsy, it's nice to know that they won't at least make people worse by giving them a drug. And some of the focal epilepsy drugs actually do exacerbate generalized epilepsy. And suddenly, you find out, "Whoops, I thought this guy was focal. Turns out that they're generalized, and now they're having lots of seizures." So that is another possibility for the future that this turns out to be broad spectrum, and that would be a big positive as well.

Thanks, Jackie. And actually, maybe I'll follow on that with a question for Mike. So Mike, you showed that slide that showed a number of different animal models, both chemically induced and electrically induced seizures in animals. And you showed both the ezogabine data and the 1101 data. Thinking about that broad spectrum of activity, if you looked at other mechanisms or other drugs available, how would you characterize other drugs in terms of broad spectrum or not when we look across a panel of animal models?

Well, I think Dr. French actually highlighted that point. The sodium channel blockers are highly effective in the maximal electroshock model, which is a model in which XEN1101 is also very effective. But the sodium channel blockers aren't effective in the, for example, 6-hertz model, the paneling tetrazole model and so forth, whereas XEN1101 has this broad spectrum of activity. It's effective not only in maximal electroshock, but also in the 6-hertz model, the chemoconvulsant models like the paneling tetrazole model and so forth. So we don't have a direct one-to-one correspondence between broad spectrum activity in the animal models and the clinic. But there's a suggestion, when you have a drug like ezogabine was that has this broad spectrum activity in the animal models, that it has a very comprehensive effect and is likely to be effective, broadly, in epilepsy patients no matter what their diagnosis.

Thanks, Mike.

Ian, just to make a quick point is that the plan with ezogabine had been as a next study in LGS trial. Unfortunately, it never got done, but Jackie will know that history well. So there was probably a missed opportunity to study it across a variety of epilepsy phenotypes. And hopefully, we can get there with 1101.

Yes. I was actually at the NIH at the time that ezogabine was coming through. And we were very excited about it because it had this unique broad-spectrum activity. The NIH team that was evaluating it commented on this as a unique characteristic. And I think that's really why ezogabine was developed. Now at the time, we didn't know that it targeted Kv7 potassium channels. That only came much, much later. And I think one important point to highlight there is that ezogabine wasn't designed as a molecule to open Kv7 potassium channel. So it has many off-target effects that aren't related to Kv7 activity. And that's probably the reason why its tolerability is low because in addition to the Kv7 mechanism, it can act as a positive allosteric modulator of GABA A receptors as well. In the case of XEN1101, it's really a targeted mechanism. It came much later in the development, and it was designed and screened essentially to specifically open Kv7 channels.

I just wanted to clarify something that you said, Simon, when you said Lennox-Gastaut. Some people on the video might not know that, that is a combined focal and generalized epilepsy. So you would not put -- in fact, that is specifically one of the epilepsies that can be made worse by giving a drug that's more narrow spectrum, such as some of the sodium channel blockers.

Thanks, Jackie.

Jackie, maybe you can comment on a question we've had. As you think about the concept of both trial and error and kind of moving patients through if they're not well controlled on monotherapy. So how long do you keep a patient on a specific therapy before you move to a second one, before you start getting into adding different drugs together?

I love the question. It's rather complex. So first of all, one has to know whether the reason for the switch is a side effect tolerability issue or whether it's a seizure issue. So if it's a tolerability issue, it depends on how bad it is. Obviously, if you have something like a rash or DRESS syndrome, you're going to have to move very quickly. Other things, you can move a little more slowly. And then as far as seizure are concerned, there's where it gets interesting because even people who are treatment-resistant have seizures that occur at different frequencies. So you could have somebody whose seizures occur every 3 months, but they're treatment-resistant or somebody who has seizures that occur every day but they're treatment-resistant. Obviously, it's going to take far less time to figure out that the daily seizer is not responding to drug than the person who's seizing every 3 months. And just imagine also that the person who's seizing every 3 months has a 50% reduction in seizures, then their next seizure might not occur until 6 months. And so it's going to take a long time to figure out that they have failed that drug. So it's really extremely individual as to how long. And I will just finish by saying that that's in the hands of people who are really paying attention and expertly watching people, whereas, unfortunately, there are many, many people in the United States who have been having frequent seizures on the same drug for a very long period of time, and their doctor will write in the chart that this person is controlled, and what they actually mean is they don't call very much.

Yes. So moving a little bit to -- moving to the attributes of 1101. So we've talked about them today. Some things we know, we know it's QD drug, one pill once a day, evening dosing. We know it's a novel mechanism, no titration. There may be potential mood impact. We talked about the broad spectrum preclinically. And obviously, we will know in a couple of months where we are from an efficacy point of view and also safety and tolerability from the unblind data. But when we think about the attributes that we know today, what excites you most about the profile and the attributes? Maybe Mike, we'll start with you.

Well, again, I'm particularly excited about the possibility that we will once again have a drug that targets this novel mechanism that I feel is really one of the most interesting among the antiseizure drug mechanisms. And I think that this drug is, so far, checking a lot of boxes, which suggests to me that it could be very valuable in clinical practice. Obviously, we won't know all of that until the drug gets out into practice and people have an opportunity to use it on an everyday basis. But so far, things look very, very good. And I'm really looking forward to having it available to use with my patients.

Thanks, Mike. And Jackie, anything to add on kind of the as you rank or you think about different attributes on what are the things that excite you about 1101?

Well, there are the things that you can know and the things that at the moment, you cannot know, right? So you're -- I cannot tell you how many drugs I evaluate even in a given year. And many of them, unfortunately, even when you get to the point of a randomized controlled trial, you already know the bad news. You already know that this drug has drug interactions or makes people sleepy or causes a rash or needs to be taken twice a day and I can go on and on and on. So just the fact that if you ask me, what's the bad news? What's the downside? I can't really come up with anything. And now I'm waiting for the good side, which I truly hope and expect will happen. But of course, we have to wait for the trial to read out. That's already putting it in a very advantageous position.

And Chris, anything from you on what we heard in market research in terms of how the broader group -- and I know you -- I know we have Jackie and Mike as KOLs on the call, but you had a lot of conversations with kind of the high prescribed -- prescribers in the community, how they think about the attributes?

Yes. No, I think that's a great point: the differentiation between key opinion leaders, who are sitting in academic centers, who are much well versed in the data, as both Mike and Jackie are. The vast majority of the physicians we spoke with don't have that level of sophistication and aren't reading academic literature and in the weeds from a profile standpoint. What they gravitated towards were the ease-of-use attributes. This is a product that is easy to add. It's easy to use. And at least to date, there are no risks. And this comes from both the drug-drug interaction side of things, safety and tolerability. But there's nothing that stood out to date that they say, "This is going to be a product that is going to worry me to add it on to a healthy portion of our patients." And that's what we heard really being the dominant feature, is that this is a product that is easy. And remember, the vast majority of the physicians and the writers are, in fact, not sitting in academic centers. They're sitting out in the community with potentially less sophistication.

Thanks, Chris. So we've talked both in the presentation, but we're also still getting questions that are coming in on kind of the comparison between 1101 and ezogabine. And so Mike, maybe I'll start with you. We know ezogabine had good efficacy in that kind of 30% to 40% range, at least at the tolerated doses of 600 and 900 milligrams daily. Obviously, I think at 1,200 milligrams, the tolerability really wasn't very good. We know the limitations of ezogabine really around the TID dosing in PK and the Cmax-related AEs, urinary and pigmentation. Maybe you can just give your perspective, if ezogabine didn't have those limitations, how widely used do you think it would have been, the excitement around the drug at the time? And how competitive do you feel ezogabine would have been, at least from an efficacy point of view today?

Well, it's hard to imagine the counterfactual because I think the community really recognized that this drug was challenged in terms of tolerability. Even at the time of the Phase II trial, we knew that there were a lot of dropouts because the therapeutic window was so limited for the drug. If you could fix that problem plus all of these other issues, including the pigment issues and the urinary retention issue, then the possibility of having a drug that has such a broad spectrum activity is really exciting to me. The gold standard broad spectrum drug is valproate, Depakote or Depakene. It's a drug that we have to use reluctantly in a sense because it's the gold standard for generalized epilepsies. But it has so many liabilities, from weight gain to hair loss to polycystic ovarian syndrome on and on, and it's a major human teratogen to boot. So having something that has a broad spectrum activity and is well tolerated and doesn't have the significant liabilities of valproate, I think, is one of the most exciting possibilities in epilepsy. Now I don't want to imply that XEN1101 is going to have broad spectrum activity. I think Jackie was very correct to be circumspect and wait until we actually have data, which is what we do. But I think we can imagine a future in which that data is available, and that puts this drug in a very different category in my mind.

Thanks, Mike. So Jackie, I know you were involved on some of the key publications for ezogabine. When you kind of think back to that time, what were your perspectives on kind of the profile of ezogabine at the time?

So many people know that my feeling was that there are drugs that -- you can only squeeze so much juice out of the orange, so to speak. And there are drugs that you know that there is a dose response relationship and you're getting better and better efficacy as you go up in dose, but the efficacy that you can get is blocked by the fact that you have adverse effects. And in the case of ezogabine and retigabine, that blocking was because of what we call peak dose side effects, which means that there was a lot of ebb and flow because it had to be given 3 times a day. And the concentration, the exposure would go up, and then it will go down and then will go up and then it would go down. And it was when it hit those toxic up-peaks that people would have side effects. And I was even convinced that if you could have retigabine/ezogabine in an extended-release formulation, you could not only get substantially better tolerability, but you could also get substantially better efficacy. And that's what we see in these short-acting drugs that -- for example, oxcarbazepine, that you get both better efficacy and tolerability when you smooth out that curve. So to the extent that even this drug is the equivalent of a sustained-release ezogabine, it would be a drug that I would want. So -- and if it's better than that, even better. So that is an exciting possibility to me.

Great. Thanks. Simon, maybe you can talk about we get questions still around the ezogabine dimerization, the pigmentation and the ability for us to convince people that 1101 can't dimerize and provide that pigmentation. So Mike did a nice job of walking through the chemistry, but maybe you can just walk through clinically. I know we haven't seen anything to date, but what we're measuring and how far out we're going to go in terms of measurement, a little bit about the ezogabine data where the pigmentation showed up. We have this concept of tail risk, but at some point, I think we're going to gather more and more data to be able to address that question.

Thanks, Ian. Just briefly. So firstly, we don't think this is mechanism dependent. I think that's important. We don't see pigmentary changes in humans that have the Kv7 gene knocked out, for example. So I think what was observed with ezogabine, as has been discussed, is really a time-dependent aggregation of these dimers, which had higher avidity for [ melamine ]. GSK presented some really elegant studies confirming that hypothesis, at least certainly looks to be the case. Pigmentation was seen in some patients kind of in that 6- to 12-month window. But mean or average was generally around a couple of years. Importantly, the pigmentation, particularly in the eye, was not deemed toxic, so the FDA softened their warning label significantly in 2015 around that. So as far as I know, KOLs may know otherwise, I've not actually seen a case or read of a case of visual toxicity reported with ezogabine. I think there were some discussions on reversibility. I think there were a number of reported cases where it was reversible on cessation of drug dosing over time as well. So the key issues, of course, for the eye. And what was interesting with ezogabine as almost a biomarker of this was the pigmentary changes in the urine that were observed. So about 1% to 2% of patients actually in clinical trials were shown to have chromaturia, which is pigmentation of the urine. We've not seen chromaturia to date, and of course at 1% to 2%, we should have seen it. So that's important because we've seen now dosed multi-hundred human subjects and/or patients, human volunteers or patients. Of course, the longer term will be the eye and skin pigmentation, which is actively being looked for, of course, actively both in the double-blind portion of the study but also in the open label. So I think we'll complete in probably on X hundreds subjects at least a year, and hopefully, a number of subjects out to 3 years, where we'll have a good degree of data where I think if we don't see it -- again, a negative is a negative, how to prove a negative. But at those types of sample sizes, we should -- we certainly would have expected to see at 3 years. Given about around 5% to 15% of patients reported on ezogabine and pigmentation, we would expect to see in multi-hundred patients out 1 to 3 years' pigmentation in some way, shape or form, including in the urine, which again, we have not seen to date. Look, this asks -- the big question I'm sure in everyone's mind is, is this going to be a label requirement? Are we going to have to have post marketing? All of that, of course, we'll discuss with the agency. But we'll certainly bring, I think, at a registration package, we'll bring to the FDA multi-hundred patients for a pretty long term on treatment, which hopefully will assuage those concerns. Certainly, we've not seen it to date.

Yes. That's a very comprehensive answer. Okay. Let's move to the competitive space. So obviously, a drug that we get a lot of questions on is cenobamate, a drug that was launched last year as XCOPRI in the U.S. So Jackie, maybe you can start. How have you incorporated cenobamate into the treatment of your patients?

Well, to date, it has absolutely become the go-to for patients, the ones that I described before who have bad epilepsy, have failed multiple drugs. If they have not tried cenobamate, we're even sort of at the point where we would say, before sending them to a surgical evaluation or before sending them particularly to have an RNS evaluation, since RNS is not as efficacious, cenobamate should be tried. So very quickly, all of the treatment-resistant patients are being tried on cenobamate.

And Mike, anything to add in terms of your practice?

Well, I think cenobamate is always going to be kind of a third-/fourth-line treatment because of this issue of DRESS, the slow titration that's required. And it doesn't have kind of the positive characteristics that a lamotrigine has that causes us to go through the trouble of doing the slow titration because we can get the mood benefits, the tolerability benefits of lamotrigine. Cenobamate is a drug that has a very narrow therapeutic window, a lot of toxicities associated with it as you push the dose. So I see that as really a specialist's product. As Jackie says, for refractory patients, it's certainly an option, given the evidence that it produces seizure freedom at a higher rate than any of the other drugs that we have available. But given the liabilities, I don't see that as moving up into the first or even second line. We would hold that one back and use it if needed, but not in the beginning.

Thanks, Mike. Staying on competition, obviously, we've had a recent FDA warning on lamotrigine and some of the cardiac liability. Has that warning changed anything in your clinical practice? Or how do you think about -- and do you think about it as lamotrigine or broader in terms of sodium channel block? Mike, maybe you can start with that one.

Well, I don't worry too much about the cardiac warning that came out recently. Many of the drugs do potentially have effects on the EKG, shortening of the PR interval for example, in some cases, or other changes. Most of the patients with epilepsy that we see are largely healthy, younger-age group patients. And so it doesn't come up all that often. Lamictal is an important drug, and we really benefit from having it in clinical practice because it's just so well tolerated.

Thanks, Mike. Jackie, why don't we move -- there's been some discussion today. And obviously, it's come up in a lot of our market research as well about the comorbidities. So maybe you could just talk about, in the patients that you see around depression and mood, percentage of patients, how you think about them as they come in, how you treat them differently than you would if someone didn't have that comorbidity and -- as broad as you want. You can talk obviously -- we talk a lot about mood and depression, but anxiety and migraine or other things that have come up.

So I have to say that patients who are depressed and anxious make their physicians depressed and anxious as well. This is particularly true because the ability to get psychiatric care for people with epilepsy is minimal. And it often -- just as with other things, with people with epilepsy, we don't give primary care, but we often give principal care, which means that we are responsible for taking care of the main issues that arise with our patients, and psychiatric ones are no exception to that. We've sort of had to learn a little bit of psychiatry in order to be able to treat them, but there is always a certain degree of uncertainty there. And so we would love to have a combined sort of treatment. And the fact that lamotrigine is a bit of a mood elevator, back to lamotrigine, certainly, has not heard it in regards to being a very favorite drug that is used by epileptologists in their patients. Moreover, there are a group of drugs that we can't use or use very hesitantly because they have a potential for worsening mood. And of course, levetiracetam is at the top of that list. Unfortunately, we find that the community doesn't always understand those things, and we often get patients coming to us with significant mood or anxiety or irritability issues who are currently taking levetiracetam. And we work to try and provide therapy that is going to improve their quality of life and improve their mood and irritability symptoms. We, as epileptologists, certainly, are very, very mindful of drugs that worsen irritability and mood. And we preach to our colleagues the same, and we will continue to and perhaps more loudly, when alternatives exist that we consider to be good alternatives.

Thanks, Jackie. Mike, anything to add from your perspective?

No. I would completely agree. I'm very focused on mood. I screen all of my patients for mood issues with the PHQ-9 routinely every time I see them. And it's just remarkable how common depression is. Maybe we shouldn't be so surprised given the stresses that we all are under today with COVID and everything else. But it's just endemic in the population. It's a particular problem for our patients with epilepsy. So I think this is on the radar screen for all clinicians. If XEN1101 -- if there's data to support the fact that it has a demonstrable mood benefit, I think that it's going to really increase the level of excitement that we're all going to have for the drug.

Thanks, Mike. I'm mindful of time. I know we have a couple of minutes left and lots of questions still. But Simon, I think we should -- one of the final questions we should talk about is really, as we get ready for the X-TOLE data in the coming months, really how we define success for X-TOLE going into that study. So maybe you can start with your perspective. I'm happy to provide my commentary, and then I think we should be able -- we should finish off with Jackie and Mike giving their final thoughts overall.

Yes. I'll be brief because I think a lot has been summarized by Jackie and Mike already. I think a drug has to work. So I think that has to work, should be in the range of existing therapies for this condition. I don't think the cenobamate efficacy bar is a requirement for a successful drug, and I think VIMPAT proves that. It's ease of use, together with a certain effect size and tolerability, I think, are really, really key. And as Mike just said, if mood differentiates -- let's not forget, up to 50% of patients with focal onset seizures have been reported to have mood disorder. So I think that success, Ian, is a once-a-day drug that's easy to take, that's easy to combine, that's well tolerated and that works as well as existing drugs and may affect mood, I think, is quite differentiated.

Yes. I mean, obviously, we talk a lot about this, and I would agree. And how we've modeled the study in terms of coming up with our powering assumptions is I'll just think about placebo in the high-dose 25-milligram arm. We've modeled a 20% reduction for the placebo patients in the monthly seizures and 35% at the high dose for 25 milligrams, that 15% separation. And really, if you think about the ezogabine data in terms of a well-tolerated dose, really in that 30% to 40% range in terms of reduction. So as we think about the study and how we've modeled it and had input from people like Jackie and Mike along the way for the last number of years, that's how we're thinking about the study. Just as we wrap up at the top of the hour, I'll give last words to Jackie and Mike, just overall thoughts on the session and any parting words and then we can wrap up. Jackie, we'll start with you.

Yes. Thanks because I actually have to go to another call. But I think that everything has pretty much been said. We're waiting very anxiously to see what the efficacy is. I completely agree with Simon that it doesn't have to be as good as or better than cenobamate because cenobamate, as Mike said, does carry some baggage with it. I think that the ease of use is going to be a very positive thing, and we already know that to be the case. And we're very much looking forward to the results of the trial.

Thanks, Jackie. And Mike, from you?

Well, I'm also looking forward to the results of the trial. Thanks so much, Ian, for having me participate in this event. I've certainly enjoyed it, and looking forward to seeing good things from Xenon coming into the future.

Thanks, Mike. And on behalf of Simon and Chris, Dr. French, Dr. Rogawski, this has been a fantastic session, I think full of education and information and a very informative Q&A session. So on behalf of all of us at Xenon, thanks for joining us. Thank you to all the investors and analysts that have dialed in.