Good morning, everyone, and thank you for joining us. We're excited to be speaking with you fresh off a highly successful American Epilepsy Society meeting for Xenon. Before we begin, please note the standard notice that we will make a number of statements today that are forward-looking. I encourage you to review our SEC filings for a more complete discussion of risks facing our business, and readers are cautioned not to place undue reliance on such forward-looking statements. After today's call, a recording of this presentation will be available on the investor section of our website at xenon-pharma.com. So joining me on today's call are Dr. Chris Kenney, our Chief Medical Officer, Darren Cline, our Chief Commercial Officer, and Tucker Kelly, our Chief Financial Officer.
I'm going to start today with some opening remarks, including an overview of our presence at the recent meeting of the American Epilepsy Society and what we heard from clinicians about the opportunity for azetukalner to meaningfully change the epilepsy treatment paradigm. Chris will then provide an overview of the data we presented at the meeting, including our latest X-TOLE Open Label Extension study data. Then Darren will provide an initial update on the progress we are making to prepare for our first commercial launch. Tucker will then join us for a short Q&A portion of the call. As a reminder, if you'd like to ask a question, you can type it into the chat box at any time. So let's get started. We have just gotten back from a great week in Atlanta for the American Epilepsy Society 2025 meeting.
As a neuroscience-focused biopharmaceutical company and a leader in ion channel drug discovery and development, AES continues to be an important congress to showcase the data that we have generated with the epilepsy community, including the latest updates on our phase 3 azetukalner program. Azetukalner, or AZK for short, remains the only Kv7 channel opener in development that is backed by long-term efficacy and safety data from clinical studies of patients living with epilepsy. We have highly compelling placebo-adjusted efficacy data in focal onset seizure patients. This is from our phase 2b X-TOLE trial, and data supports durable and sustained efficacy over time through our open label extension study. We now have more than 800 patient years of exposure and safety data.
AZK leads our pipeline, and we view its Kv7 MOA as a pipeline and a mechanism, given its potential to reduce the neuronal hyperexcitability present in multiple neurological disorders. First, it has broad spectrum potential in epilepsy, and we are investigating it in focal onset seizures in our X-TOLE2 and X-TOLE3 studies, as well as in primary generalized tonic-clonic seizures in our X-ACKT study. As a reminder, our X-TOLE2 study is fully enrolled with 380 patients randomized, and we look forward to our first AZK phase 3 top-line data readout in early 2026. If approved by the FDA, AZK would be the only Kv7 drug available for the treatment of epilepsy. We are also focused on broadening therapeutic opportunities for AZK beyond epilepsy, where we have strong preclinical, clinical, and genetic evidence supporting its development in neuropsychiatric indications.
We have therefore also advanced AZK into phase 3 studies in major depressive disorder and bipolar depression, conditions which impact millions of patients and where novel treatments are urgently needed. But the pipeline we're building is also much broader than AZK. We are advancing several promising early-stage ion channel programs, including two molecules in phase 1 clinical development for potential pain indications, XEN1120 targeting Kv7, and XEN1701 targeting the sodium channel Nav1.7. Additionally, our preclinical Nav1.1 program reflects our expanding commitment in epilepsy, with preclinical data suggesting that targeting Nav1.1 could potentially address the underlying cause and symptoms of Dravet syndrome while providing the convenience of oral dosing. Overall, our pipeline reflects enormous potential to impact the lives of patients and to grow the overall value of our company. Our progress on AZK and our growing leadership in epilepsy was front and center at AES 2025.
We have been to many AES meetings over the years, but this was by far our most impactful meeting yet, based on the data we showcased and our interactions and knowledge sharing with the community. We presented seven posters, including 48-month X-TOLE open label extension data, real-world epilepsy studies on the burden of depression and ASM titration on patient care, and an update on our Nav1.1 program in Dravet syndrome. One of our real-world depression posters was selected by AES as part of their official press program, underscoring the increasing clinical importance of mental health in epilepsy care. Through our on-site activities focused on HCPs and advocates, we had about 1,500 total engagements where we presented and discussed our AZK data, including through on-site meetings, our poster presentations, and our scientific exhibit.
Another highlight of our symposium was on depression and anxiety in epilepsy, and this was held in partnership with the Epilepsy Foundation of America, as well as three leading epileptologists. This was with Dr. Jacqui French, from the NYU Langone Comprehensive Epilepsy Center, Dr. Andy Kanner, from the University of Miami Miller School of Medicine, and Dr. Heidi Marie Munger Clary, from the Wake Forest University School of Medicine. But the greatest joy from AES is always the opportunity to speak directly with physicians who have experience with AZK and hear stories of the benefits that some of their patients are having in the study. Many physicians shared with us that they have patients who are experiencing seizure freedom for the very first time in their lives, and they tell us that the ways that this is impacting their independence and the quality of life.
The growing dataset for AZK, representing more than 800 patient years of efficacy and safety data, continues to resonate with clinicians, and we heard this time and again in our discussions throughout the meeting. Out of these discussions, there's really three themes that continue to rise to the top. Number one, they view AZK as highly effective, having achieved the strongest placebo-adjusted efficacy in the X-TOLE double-blind period, and this is despite being in the most refractory patient population ever trialed in epilepsy. In the open label extension, sustained MPC reductions in focal seizures were over 90% at 48 months, with 100% monthly seizure reduction at 48 months for those patients who are on either one or two anti-seizure medicines at baseline.
Additionally, AZK's potential as being mood-neutral or mood-positive is compelling, given the number of ASMs that can negatively impact mood, as well as the growing recognition of depression as a complicating factor in epilepsy care. Number two, they also appreciate the fast onset of effect, with efficacy demonstrated at week one and the ability to start at a therapeutic dose. This is in contrast with other ASMs where clinicians must start low and go slow, taking several weeks or even months to reach therapeutic levels. And third, they view AZK as easy to add into a patient's treatment plan. As a Kv7 modulator, it has a novel mechanism, and this can be used in combination with foundational ASM treatment. As per the study protocol, AZK is dosed orally once a day with food and requires no titration.
They view AZK's lack of meaningful DDIs and no monitoring requirements to be an additional plus. Today, you will also hear that this profile resonates strongly with both epileptologists and general neurologists, which is, in our view, meaningfully supports the potential commercial trajectory of AZK. We expect to launch AZK first in focal seizures, as is common with any branded epilepsy launch, and it will likely first be used by epileptologists and initially in more refractory patients. However, we believe the opportunity for growth with general neurologists is significant, as is the opportunity for earlier use in less complex patients, and this is being supported through our OLE data. We would expect that continued growth would occur through label expansion into PGTCS.
Although AZK has significant commercial potential just in the epilepsy category, we do believe that there is a great opportunity for use as we explore the differentiated profile of AZK in neuropsychiatry. This could be proven through our phase 3 programs in MDD and in bipolar depression with positive data, resulting in future indications with significant market potential. Coming out of AES, we are energized by the opportunity for AZK to meaningfully impact the lives of people with epilepsy. We heard great enthusiasm about the latest data and AZK's attributes, and we are continuing to raise the profile of AZK and Xenon with HCPs and advocacy groups. With the phase 3 data on the horizon for early 2026, it is truly an exciting time for Xenon, for patients, and for the clinicians who care for them.
So now I'm going to turn the call over to Chris, and Chris can walk us through the latest data from AES. Chris, over to you.
All right, thanks a lot, Ian, and good morning to everyone. While we advance our phase 3 studies in epilepsy, we also remain focused on scientific exchange and education around the profile of AZK seen to date. Ian mentioned AES. At AES, it continued to be gratifying to remind everyone of the compelling double-blind efficacy data from our phase 2b X-TOLE study, which we believe demonstrated the best placebo-adjusted results ever seen in a clinical study of focal onset seizures. Specifically, after eight weeks on treatment, we saw statistically significant and dose-dependent reductions in focal seizures, with the highest dose cohort seeing about a 53% change from baseline compared to an 18% change in the placebo one. The responder rate was approximately 55% in the same cohort.
Also, in X-TOLE, we observed a rapid onset of efficacy at week one in all AZK doses tested, data which are very compelling to clinicians who are used to lengthy, complicated titration regimens for almost all the other anti-seizure medications. AZK was generally well tolerated in the double-blind period, with adverse events consistent with commonly prescribed anti-seizure medications. The most common treatment-emergent adverse events across all groups were dizziness, somnolence, and fatigue, while the most common adverse events leading to discontinuation were dizziness, balance disorder, dysarthria, and gait disturbance. Serious adverse events were low and balanced across groups. Now, moving on to data we presented at AES 2025. As Ian mentioned, we presented seven posters.
Two posters pertain to our 48-month X-TOLE open label extension, or OLE, data, including an analysis characterizing intervals of seizure freedom, which we believe presents a clinically relevant view of seizure freedom with the potential to be practice-changing. Additionally, we shared four real-world studies highlighting significant challenges in the successful management of epilepsy, depression, and ASM titration. We also shared an update on our Nav1.1 program in Dravet, which in Dravet mice improved motor performance, suppressed spontaneous seizures, prevented SUDEP, or sudden death, led to more mature dendritic spine morphology, and also increased long-term potentiation, which is a potential correlate for learning and memory. These data underscore the incredible potential of our Nav1.1 approach to address the underlying cause and symptoms of Dravet syndrome while providing the convenience of oral dosing.
We're excited that this program is now progressing through IND-enabling studies, and the epilepsy community is also encouraged by its great potential. First, I'll highlight our latest interim data from the X-TOLE OLE, which are now out to 48 months. For the 131 patients who were treated for at least 48 months, median percent change reduction in focal onset seizure frequency from baseline increased to about 91%. As evidence of AZK's impact in less complex patients, those who were taking just one or two anti-seizure medications at baseline saw 100% median percent change reduction in focal onset seizure frequency at month 48, compared with those receiving three anti-seizure medications at baseline who saw an approximate 82% median percent change reduction at the same time point. This strongly supports the potential use for AZK in earlier lines of therapy.
All in all, the OLE data demonstrate that efficacy continues to improve the longer patients are on drug, which bodes well for long-term retention in a commercial setting. Our latest responder rate data also continues to support improving efficacy with longer treatment. Among OLE participants treated for at least 48 months, about 83% had at least 12 consecutive months of at least 50% reduction in seizure frequency, and about 44% had at least 12 consecutive months of at least 90% reduction in seizure frequency. We also continue to see improvements in seizure freedom. Any consecutive 12 months of seizure freedom was attained for about 21% of participants entering the open label extension, and about 38% of participants treated for at least 48 months. Approximately one in 10 treated for at least 48 months had 48-plus months of seizure freedom.
These results are quite remarkable and incredibly meaningful when you keep in mind that many of these patients are achieving long periods of seizure freedom for the very first time in their life, and that they had significant baseline seizure burden and had failed numerous ASMs prior to entering the X-TOLE study. Now, our second open label extension analysis at AES was an exciting and clinically relevant exploration of seizure freedom, which may help guide future clinical decision-making. To our knowledge, this was the first time this type of analysis had been completed for an experimental new medicine in epilepsy, and it generated a significant amount of interest on the ground for its real-world applicability. As background, seizure freedom is a primary goal of epilepsy treatment, but patients may define expectations for seizure freedom differently based on their circumstances.
It's common for patients to experience a fluctuating clinical course of attaining and regaining periods of seizure control. This may occur due to provoked seizures, perhaps due to missing a medication dose or multiple doses, poor sleep, et cetera, or it may also occur due to an unprovoked seizure. Understanding patterns of seizure freedom following a breakthrough seizure can guide patient expectations and help better characterize dynamic patterns of treatment response. This analysis, therefore, asks two questions. One, can long-term seizure freedom be attained with AZK? And two, if it is lost, can it be regained? On this slide, we see an analysis from a subset of patients in the OLE who were treated for at least 48 months and who reported at least 12 months of seizure freedom at the time of last study visit.
About one in four patients had 12 months of seizure freedom, and of those patients, 75% had at least 24 months of seizure freedom, and about 64% had at least 36 months of seizure freedom. This analysis reinforces the strong seizure freedom results from the broader open label extension study. The second part of our analysis looked at those who'd attained seizure freedom already for at least six months. Now, six months is a highly relevant time point for people living with epilepsy because in many states, if one has been seizure-free for those six months, it means they can regain the ability to drive. In this analysis, half, about 47%, continued to experience seizure freedom, while the other half subsequently experienced a seizure.
Among those who experienced a seizure, 70% were able to regain at least six months of seizure freedom, and 58% were able to regain at least 12 months of seizure freedom. These compelling data make the case for continued treatment with AZK, even in the event of a breakthrough seizure, which can be common during the course of an epilepsy patient's journey. Shifting to safety, the OLE has now generated more than 775 patient years of safety data. In total, through 48 months, treatment-emergent adverse events and treatment-related treatment-emergent adverse events occurred in 89.5% and 65.8% of the safety population, respectively. The most common adverse events included dizziness, headache, COVID-19 infection, somnolence, fall, weight increase, memory impairment, and gait disturbance. Four participants reported urinary retention, and no dose changes were made in any case.
Serious treatment-emergent adverse events occurring in more than one participant included seizure, deep vein thrombosis, paresthesia, seizure cluster, influenza, pneumonia aspiration, rhabdomyolysis, and fall. Overall, the long-term safety profile in the open label extension remains comparable with that observed in the double-blind period. In addition to our AZK-OLE data, we also presented three real-world studies on the impact of depression in epilepsy care, which underscores the need for mood-neutral or mood-positive anti-seizure medications. In the first study, patients with focal seizures reported a considerable mental health burden, with more than 80% of patients surveyed reporting depressed mood and anhedonia, and 42% reporting suicidal ideation. In the second study, surveyed patients with focal seizures and depression symptoms reported worse quality of life and higher healthcare resource utilization, including two times as many emergency room visits and five times as many inpatient hospitalizations as those without depressive symptoms.
In the third study, a retrospective claims analysis among patients newly diagnosed with epilepsy found that depression was associated with shorter duration of initial therapy and an increased risk of initial treatment failure. This last poster was selected by AES as part of their official press program, underscoring increased recognition of the clinical burden and impact on treatment posed by depression. Overall, these studies reflect the importance of considering the whole patient, inclusive of mental health status when making treatment decisions, and the importance of tailored treatment strategies for these patients. Secondly, we also know that there are several mainstay ASMs that may exacerbate depression, anxiety, or other mood disorders, and the data reinforce the importance of developing mood-neutral or mood-positive therapies, which we believe may be a potential benefit with AZK.
The final presentation I will highlight is our real-world study on clinical practice and patient burden associated with ASM titration. It is important to note the vast majority of ASMs require some type of titration period, ranging from weeks to months to improve tolerability. This titration phase can delay reaching the therapeutic dosing and seizure control, and it can be challenging and confusing for patients, potentially leading to non-adherence. This poster recaps titration insights from a patient survey and physician roundtable conducted by Xenon. In the survey, patients reported significant challenges related to titration, including time required and increased number of clinic visits, keeping up with dose adjustments, and difficulty understanding the whole titration process. They also reported significant concerns while titrating, including being worried about their risk of developing a focal seizure. The HCP roundtable reinforced themes from the patient survey.
During cross-titration, HCPs reported balancing multiple, often competing considerations, such as medication burden with safety and tolerability. They also reported increased strain on healthcare resources, such as additional follow-up visits and visit time, needing additional staff, and increased coordination with the pharmacy and communication workload to check in with patients. All in, this study identified the significant burden that titration places on both patients and providers. It also reinforces multiple dimensions of value for an anti-seizure medication that doesn't require titration, which, again, is a rarity in the current treatment paradigm and which could set AZK apart from others. In conclusion, we're very proud of this multidimensional set of data at AES 2025 that highlighted our leadership in epilepsy, as well as the compelling attributes that differentiate AZK and would potentially change the treatment paradigm in a meaningful way.
We continue to see strong efficacy in the open label extension at 48 months, including a 91% median percent change reduction in monthly seizure frequency and a 100% reduction among those receiving one or two anti-seizure medications at baseline. We also are seeing impressive seizure freedom rates and the ability to maintain and regain long periods of seizure freedom with AZK. Safety and tolerability remain comparable to the double-blind period. Our real-world studies highlight that depression and anti-seizure medication titration presents significant challenges in epilepsy care, reinforcing the opportunity for a mood-neutral or mood-positive anti-seizure medication without a required titration regimen and with a rapid onset of efficacy, which we believe AZK can provide. I'll close by echoing what Ian said about the joy in hearing from clinicians about their experience with AZK at the American Epilepsy Society meeting.
It's important to remember that our data is made up of many individual stories of people who have struggled for a long time with their seizures and the loss of independence and quality of life that comes with them. We're incredibly inspired by these stories of the patients who are achieving seizure control and seizure freedom for the first time in their lives, and we're excited about the potential to deliver a long-awaited new therapeutic approach to the community. Now, I'll pass the call over to Darren to discuss how he and his team are preparing for the potential commercialization of AZK. Darren.
Thanks, Chris, and good morning, everyone. It's been an exciting and busy six months since I joined Xenon and have continued our work to prepare for top-line data and potential commercialization of AZK and focal seizures.
Working closely with Chris and the medical team, we are validating our market analysis and identifying unmet needs among patients and providers. These insights are guiding us as we build a comprehensive plan to ensure a successful launch for AZK. Stepping back to consider the broader landscape, epilepsy is defined by recurrent seizures, which may be either focal or generalized in nature. It stands as the fourth most prevalent neurological disorder, surpassing both Parkinson's disease and multiple sclerosis in frequency in the United States alone, with approximately three million adults affected by epilepsy, with 1.8 million experiencing focal seizures. The impact of this condition is significant. Individuals living with epilepsy often face elevated rates of anxiety, cognitive challenges, reduced quality of life, and a heightened risk of injury and premature death compared to the general population. Importantly, the effects of epilepsy extend beyond seizures.
Research indicates that up to half of those with epilepsy may develop symptoms of depression, which can further hinder their ability to achieve optimal seizure control. Our own real-world studies suggest that the prevalence of depression among epilepsy patients may be even greater, a finding echoed by physicians in clinical discussions. At the recent AES meeting, multiple studies, including those from Xenon and others, underscored the complex bidirectional relationship and biological link between epilepsy and depression. Additionally, at our symposium with the Epilepsy Foundation of America, we heard incredibly emotional stories from individuals with epilepsy who have also struggled with depression and who shared the significant impact it has had on their lives. Treatment decisions for epilepsy are inherently complex and tailored to each patient's unique needs. The primary objective is to maximize efficacy while ensuring tolerability.
Most patients begin with foundational anti-seizure medications, typically a generic sodium channel agent or an SV2A modulator. While some individuals achieve good seizure control with these options, many require additional therapies or adjustments to manage side effects, including those affecting mood. These ongoing adjustments often result in switching medications or adding new ones to the regimen. Comorbid conditions, including depression and anxiety, influence prescribing decisions, as some ASMs can worsen existing comorbidities. Despite the availability of more than 20 anti-seizure medications, there are only a handful of distinct mechanisms. The lack of new therapeutic mechanisms limits opportunities to improve seizure control by combining distinct approaches. Achieving sustained seizure control becomes increasingly challenging as patients progress through multiple lines of therapy. Ultimately, about half of people with focal epilepsy remain uncontrolled, highlighting the urgent need for innovative treatment options with diverse mechanisms of action.
Now, the landscape of prescribers of branded ASM encompasses epileptologists, general neurologists, and advanced practice providers, or APPs. In the United States, approximately 80% of epileptologists prescribe branded ASMs. These are significantly more general neurologists, and about one-third prescribe these ASMs. APPs also contribute meaningfully to ASM prescriptions, while branded use among APPs is currently more limited. It is steadily increasing, particularly in offices where they work alongside high-prescribing neurologists and epileptologists. A key insight as we prepare for commercialization is the substantial opportunity for prescription growth among the general neurologists and the APPs, a perspective consistently reinforced by our expert KOL advisors. Our commercial team's prior experience launching epilepsy brands further supports the importance of targeting this diverse mix of prescribers to drive a successful launch. Our market research has further validated the potential for AZK to appeal to both epileptologists and general neurologists.
On this slide, you will see qualitative market research among these two clinician groups, where they were presented with a targeted product profile for AZK, labeled Product X here, alongside the newest branded ASM. When asked to consider the potential attributes of Product X relative to other ASM, both epileptologists and general neurologists perceived Product X to be highly favorable. Interestingly, favorability for Product X was driven by different components of the target product profile for each group. Epileptologists most often called out the novel mechanism of action, which would enable flexibility and the ability to administer rational polytherapy. They also appreciated dose-level flexibility to balance safety and efficacy, and they viewed the efficacy data to be on par with the comparator ASM. The neurologists' favorable opinion of Product X was driven by its ease of use, with no titration and limited drug-drug interaction.
They also viewed the safety profile as manageable and called out the fast onset of action, and you'll see in one of the quotes, one of the neurologists noted that the profile supports being used as a second or third-line agent, which is aligned with the earlier use supported through our recent open label extension data. This qualitative research study aligns well with other market research we've conducted, which found that general neurologists often hesitate to prescribe some branded ASMs due to the complexity. However, AZK's differentiated profile may enable them to retain more epilepsy patients in their practice rather than referring them out the care as the care becomes much more complex. Ultimately, our advisors believe AZK could become the preferred branded ASM for general neurologists, supporting broader adoption and improved patient outcomes.
It is this differentiated clinical profile that we believe may position AZK for a very successful launch. As we look at attributes that contributed to the most successful ASM brands, they include some mix of strong efficacy and manageable safety and tolerability, novel MOAs, broad spectrum effects, mood neutrality or positivity, and ease of administration. In our case, AZK may demonstrate many, if not all, of these attributes. The other common denominators in successful ASM launches include early commercial investment and an experienced launch and lifecycle management team, which is guiding our current commercial readiness efforts. Our team is deeply focused on understanding the epilepsy market, the prescribing environment, and the factors that influence access to new therapies.
We are investing in research and analysis to build on our knowledge from previous product launches and to identify innovative strategies that address the needs of both prescribers and patients at launch and beyond. For example, we have mapped the patient journey in detail to pinpoint key pressure points and opportunities for early intervention, including positioning AZK as a complementary add-on therapy. We have also conducted extensive research into the challenges associated with titration and are exploring how AZK's lack of titration requirements can be leveraged as a meaningful advantage. As we continue this work, it is clear that AZK's potential ease of use attributes will be essential for expanding adoption beyond epileptologists to general neurologists. Additionally, our market access research is guiding us to innovate and streamline the process of making AZK available, ensuring that payers recognize its strong value proposition.
Looking ahead, we plan to harness the power of emerging technologies, including artificial intelligence, to support a successful launch. These advanced tools, unavailable during previous epilepsy launches, will enable us to focus our engagement and communication efforts with unprecedented precision and efficiency. One area I'd like to further highlight is our commitment to driving innovation in our channel and patient services to support both adoption and long-term retention of AZK. Our approach centers on creating straightforward, positive experiences for healthcare providers, ensuring broad and efficient payer access, and streamlining the patient journey from initial prescription through ongoing therapy. By maximizing the success rate at the first fill and building robust resources for compliance and support, we aim to make it easy as possible for patients to start and remain on AZK and continue benefiting from treatment.
The latest OLE data showing sustained improvement with extended therapy further reinforce the importance of investing in services and infrastructure that help patients stay on AZK over the long term. The final cornerstone of our early investment strategy is assembling an outstanding launch and lifecycle management team. I'm delighted to share that we recently added a senior vice president of sales and marketing to our leadership team, with whom I personally have a successful history of collaboration from our time at GW, where he was the first commercial employee in the U.S. and played a pivotal role in building the team. Prior to joining Xenon, he led the Epilepsy franchise at Jazz for five years following GW's acquisition. He also brings a deep expertise from the successful launches of Keppra, Vimpat, and most recently, Epidiolex. The enthusiasm among physicians at AES regarding his addition to our team was truly energizing.
In addition, our customer engagement lead has spent the last 18 months strengthening relationships with centers of excellence and leading epilepsy key opinion leaders. Our market access team is also expanding and will begin proactive outreach to payers in 2026 to educate on AZK's unique value proposition well ahead of launch. I also want to recognize the growing leadership within our medical affairs group, with whom we are working closely on all launch planning. Earlier this year, we also added a senior vice president of medical affairs to our team, who reports to Chris and previously led the North American Medical Affairs Organization at Biogen. Under his leadership, we are also expanding our team of medical science liaisons in 2026, and these MSLs are engaging daily with epilepsy clinicians across the country.
These investments and team expansions are foundational in our ambition for a strong commercial launch of AZK and long tenure as a highly impactful epilepsy brand. In summary, our vision is to establish Xenon as the next leader in epilepsy with a robust package of clinical data, including the upcoming X-TOLE2 phase 3 results, the unique potential attributes of AZK, and our early investments in customer engagement and market readiness. We are extremely well-positioned to transform the care and access paradigm for healthcare providers, patients, and payers. We are highly optimistic about our ability to achieve this goal and drive meaningful change in the epilepsy community. Ian, I'll pass it back to you.
Great. Thanks, Darren. Thanks to both you and Chris for providing your perspectives on both the data as well as AES. So I'm going to just summarize on what we heard on today's call.
So our AES data reinforce the key differentiating attributes and potential of AZK and an opportunity to be a disruptor in the landscape. We believe our commercial opportunity is significant, with potential for rapid adoption by epileptologists, as well as general neurologists and APPs. And we are investing early into the insights, the innovation, infrastructure, and integration of transformative leaders into our organization to support a highly successful launch. It is certainly an exciting time for Xenon and for the broader epilepsy community as we prepare to announce top-line phase 3 data from our X-TOLE2 study in early 2026. We are optimistic for a positive outcome, and we believe that X-TOLE2, together with the strong results from X-TOLE and our open label extension, will serve as the basis for a new drug application in the U.S. for AZK in focal onset seizures.
And we look forward to keeping you updated on our progress as we move into 2026. So with that, we're now going to open the call up for questions. So as discussed at the beginning of the call, please submit your questions via the chat function. This is found below the slide window. We've had a huge number of questions that have come in already, so thanks for that and continue to do it. We're going to do our best to get through as many of them as we can, but we'll keep to the time at the top of the hour. So it looks like there's, I'm going to kind of group these questions by theme. A number of questions have come in both on the clinical side as well as commercial.
So maybe we'll start clinical more at a high level with some of the questions, and then we'll dig a little bit deeper. So Chris, let's start with you. We've had questions of just really some of our analysts and investors had the opportunity to see us at AES, but not everybody. So maybe it's a good opportunity for you to provide your perspective of really what was the feel on the ground and maybe what your biggest takeaways were from the meeting.
Yeah, sure. Happy to do so, Ian. Yeah, AES this year was a really big year. I would actually characterize it as sort of a transformational year for us in the sense that for a couple of reasons.
I mean, number one, it really had a strong sense that others were seeking us out and also now presenting the data in a manner that is more kind of focused on what a prescriber would think assuming the drug's approved, so to be more specific, we had our biggest presence yet. We had more than 50 employees across medical, corporate, commercial, and keeping track of our metrics. We interacted with about 1,500 unique different people across the board, so at our booth, scientific exhibit, and other side events. There were some people, healthcare providers, that we met for the first time, but a lot of people were quite aware of Xenon and quite aware of AZK and also asking a lot about the timing of phase 3 data and all that, and also the potential timing for an approval if we're fortunate enough to end up in that situation.
The biggest thing I think we all heard was the need for a novel mechanism, and there's a lot happening in research, a lot of it's really quite exciting, but as you look at basically all of the other drugs, investigational agents, they're not really going after mechanistic diversity per se, and when you consider that something like half of the patients with epilepsy still live with uncontrolled seizures and these mechanisms are basically already on the market, it leaves a void, so there's a lot of excitement about Kv7 as a unique mechanism that has the potential to address neuronal excitability and be used in combination with the other foundational therapies alongside all the attributes that you've heard about over the past hour or so.
Great. Thanks, Chris. We had a detailed question just that I'm happy to address on the timing for X-TOLE2.
Currently, our external guidance is that data for X-TOLE2 will be available in early 2026. I know we've shared with a number of you. We will narrow that guidance. Not quite yet, but we will narrow it shortly. The last patients in X-TOLE2 are just going through the double-blind period right now. As you heard from us on our last quarterly call, we've kind of talked through the progression of a patient from baseline to the randomization visit to the double-blind and into open label extension and how that impacts the timeline. Yeah, we're happy to narrow that guidance as we get closer to the X-TOLE2 data. Chris, one of the decisions that we made a number of years ago was to extend the open label extension from one year and then three to five.
We now have the seven-year open label extension for azetukalner, which I think is providing us with a huge amount of information and data. So maybe from your perspective, as you've been at the company a number of years as a neurologist and spending time with the epilepsy community from the double-blind into this huge amount of open label data, anything changed from your perspective in terms of the overall profile of the drug?
Well, I would say we're looking at a cutoff every year of this seven-year open label extension. And for largely, at least in terms of the traditional way we've looked at the data, I would just say that it's remarkably consistent with previous data. We're optimistic that what we saw in the double-blind period, what's happening in the OLE is reflective of the double-blind period.
I think that the seizure freedom analysis that we conducted meaningfully added to how we think about using AZK in the clinic. I really think that this idea, looking at breakthrough seizures, which do occur at times, that can be taken as a signal that a medication isn't working or a regimen isn't working, and perhaps it's time for a change. What we're seeing in the data is that there are these long periods of seizure freedom that can be regained after a breakthrough seizure, which is really meaningful and supports maintaining patients on AZK. So I was commenting about it being a transformational year. That, I think, is one of the big changes. We want to start looking at the data in a manner that will be helpful for prescribers going on the assumption that AZK ends up being approved.
Great.
There's been questions, maybe going a little deeper into the OLE data. So I'll start on some of the seizure freedom analysis, and then there's some more detailed questions just about retention rates and other things that we're seeing in open label. But maybe as it relates to the seizure freedom data, let's start there. So we presented two seizure freedom posters at the meeting. We had the 48-month OLE data cut, and then there was one on kind of a different seizure freedom analysis. Maybe could you just help walk us through the difference between the two and why we did the second one, which was a new analysis for us?
Yeah, sure. Absolutely. So I mean, the two posters, they're separate posters because they're really looking at seizure freedom from two different perspectives.
So the typical annual update that we do at AES. So we showed the 48-month OLE data cutoff with Dr. Jacqui French presenting. And we looked at patients who had at any point in time 12, 24, 36, or 48 months of seizure freedom. So that means we looked to see if they had a period of seizure freedom basically at any point. And that's a traditional way of looking at it. That's how we've done it in the past. Now, the feedback that we've gotten is, Chris, you know as well as we do that you don't ask somebody how they were doing in 2022. You ask them how they've been doing since the last visit, or you ask how they've been doing, "Have you been seizure-free over the past year?" So in the poster with seizure freedom that Dr.
Danielle Becker presented. We looked at the patients who are in the study right now. There are 131 of them at the 48-month cutoff and asked the question, "What does seizure freedom look like now?" And in that study at that cutoff date and time, which was earlier just a few months ago, we saw that more than a quarter had been seizure-free for at least 27 months, which is pretty remarkable. It was like 27.5%. And that's something that has really, I mean, when you share that data with physicians, they really pay attention. So the seizure freedom analysis also looked at patients who had reached 48 months and then had attained at least six months of seizure freedom to see if they continued to be seizure-free or if they had a breakthrough seizure. And if they had a breakthrough seizure, then what happened?
And as it turns out, about half had a breakthrough seizure. However, 75% of the group that had the breakthrough was able to regain a long period of seizure freedom afterwards. As I mentioned, looking at seizure freedom at six months is highly relevant for patients as it may free up the opportunity to be able to drive. So it's a much more clinically relevant way of looking at seizure freedom to help clinicians and patients make informed decisions if a breakthrough seizure occurs, which can happen. It might be unprovoked, or it may be provoked because of sleep deprivation or missed doses or what have you. So yeah, so those are the two posters: kind of a traditional approach and then a much more practical approach that hopefully will help out prescribers going on the assumption that AZK is approved. Thanks.
Oh, and then do you want to talk about the retention, Ian,
well, yeah. Why don't we go to. There's kind of two more kind of more detailed questions on the open label extension. One was just on the retention rates, so now that we have the population of 48 months, so maybe you can just kind of make a comment on retention, and then the second one is obviously not everyone staying in the open label extension, so there's often this question around ascertainment bias. Are you really enriching for the patients that are doing well, and I know we've had that question from our advisors and clinicians, and we've done some work there and have our thoughts there.
Yeah, sure, so yeah, you're right. They're connected.
So on retention rate, just from a qualitative perspective, if you look at the open label extension data over the long term that's available for other ASMs and you superimpose our retention data, I would say that in general, our AZK is fairly consistent with other ASMs around the one-year mark. What we see, though, is that there's a bit more stickiness. There's a tendency for people to stay on the drug more than other open label studies. Now, there are a bunch of caveats there. Hard to compare one study to another, but that's the overall pattern. Now, to be more quantitative, at a year, we're seeing about two-thirds of patients are still in the open label. And now we're four years out, and we're seeing not quite half that are still on the open label. So really quite pleased with the retention.
I'm sure that ties into the themes we've been talking about, which is tolerability that was consistent between the OLE and the double-blind, and then also some of the dramatic decreases that we're seeing in median % change seizure and also seizure freedom. So that's kind of the retention bit. Yeah. So ascertainment bias comes up, which makes sense. And just to be clear that we're all talking about the same thing, basically, the idea is that the people who stay in the open label are staying in the open label because they're doing well, and people who haven't done well drop out, and therefore your data has a bias, an ascertainment bias. So we've spent a lot of time on this. Jacqui French and others have been bringing this up really for years at this point. So to get to the bottom of it, this is what we did.
We took a look at patients and looked at the seizure reduction, whether they were in the study for a relatively short period of time, say less than six months, versus 12 months, 18 months, 24 months. And then we essentially superimposed those lines over the graph that you see all the time with the OLE seizure frequency over time. And what we see is that they're nearly superimposable. Now, there is a little bit of a tendency for more improvement in median percent change in seizure frequency for those who've been in the study longer, but it's pretty close. And so our interpretation of that is, sure, I think that to some degree, ascertainment bias explains why they're doing better over time, but it isn't the only thing that explains.
It does look as though patients who stay in the study for a prolonged period of time are doing really well.
Great. Thanks, Chris. All right, Darren, why don't we move to you a number of questions that are more commercially focused. So as you mentioned in your prepared remarks, you've been at the company six months and now back at an epilepsy company and back at AES. And I know a number of the folks on your team also back at AES supporting Xenon. So maybe just overall at AES, but more specifically, you're now have been on board to kind of evaluate what you think are the key differentiators and factors that are going to make AZK a commercial success.
Yeah, thanks, Ian. And yeah, it was just so tremendous to be back at AES and to see so many familiar faces.
And one thing that was really striking to us as the team is the emergence of Xenon and particularly AZK as the next opportunity to treat these patients with focal seizures. And it was just really remarkable the excitement that physicians have. Yeah, and I think so we're thinking about kind of differentiation at launch. And I think we think about it in a couple of different ways. I think the first is, how do we maximize this just exquisite, unique profile of AZK? And as you've heard today, we're starting to think about how we target different mix of clinicians. And if you think about historically the launch trajectory of Vimpat and Xcopri, I think you see a much broader uptake of Vimpat with the general neurology community.
And I think that what we heard over the weekend with our many engagements was our profile more closely parallels the Vimpat. I mean, just the ease of use was predominant over the weekend. And I think from a general neurology perspective, I think they've struggled with the use of Xcopri in their community settings just due to the complication of the titration and the risk of drug-drug interactions. And that came up pretty resoundingly over the weekend. And it puts a—you're titrating up, you're also having to titrate down other medications. And with really no guideline to do that, every patient is so individualized. And it puts an enormous burden on them. And not only them, but most importantly, their patients.
So with AZK and the lack of titration and DDIs, we think that, as the research showed that you saw today, we have a real opportunity to leverage the ease of use, the no DDIs, and no titration. So that's the first part. And the second, and I also alluded to this, is really it's the patient, prescriber. It's their experience. And it's so critically important that that is maximized. And the prescriptions, once it gets written, it's easy to access. They can refill their prescriptions and continue on the therapy. So as I said, we'll be looking at innovative ways to do that to ensure that, because it takes a lot of work to get that prescription written. And so how do we maximize our access strategy? And we feel pretty good about how we're thinking about that for the future. Do you want to follow up, Ian?
Oh, sorry, Darren. I was on mute there for a second. Yeah. We had the poster on titration. I know you've done with your team some Ad Board work on it as well. And we know that AZK doesn't need to be titrated. But there's been a question just on we're going to have multiple doses on label. Maybe how do you just think about having what would be on label and then how you think that's going to be received and then really used in the real world?
Yeah. We spent a lot of time with our advisors this weekend talking about that. So if you look at the data from X-TOLE, the doses are 10, 20, and 25, and X-TOLE2 will be 15 and 25. And so traditionally, epileptologists and general neurologists, because the patients are on multiple medications, they like to take that kind of lower-dose approach.
And so I think as we kind of outlined and asked what they'd like to see, that will be a similar approach with AZK. I think one differentiation, though, is because we'll potentially have four different doses available, we have the fast onset of action. And when we see what we see, or ultimately what the results are with the 15 and 25, I think that those different dosing options will be very advantageous for an epileptologist and general neurologist to start a dose and then, as quickly as they see fit with their patients, be able to really hit the adequate dose to what we all want is to really control seizures and can we get to seizure freedom. So we see it as a benefit, and our advisors tell us the same.
Thanks, Darren. So we're sitting here kind of at the end of 2025.
We all have our phase 3 data early next year, and obviously, you're doing a huge amount to prepare for launch, so let's fast forward to kind of launch. Maybe you can just walk through what the market looks like at that time from a competitive point of view on the branded side and where you think we'll fit in.
Yeah, so when we do launch AZK, it'll be seven, eight years between the last branded medication was approved. There are currently two branded currently available. We have one, Briviact, which will go off LOE next year, and so it'll be just us and Xcopri. And they'll have quite a bit more commercial experience than us at launch.
But I think what we're starting to see in the emerging data, particularly with X-TOLE, which was the strongest placebo-adjusted efficacy in a double-blind period, as Chris pointed out earlier, and our continued OLE data demonstrating that even the less complex patient taking one to two ASMs at baseline had such great seizure reduction, 100%. I think this really strongly, when we are approved, when we launch, we'll really be in a good place. And I keep anchoring back to what just resonated over the weekend was the attributes. It's daily dosing, fast acting. And I think we can't underappreciate the lack of drug-drug interactions and the lack of titration as really, really being a benefit to prescribers and their patients.
So I think along with our things that we continue to focus on around payer access, affordability, those different types of attributes, I think we'll be in really good shape for. And I think lastly, too, I'll say that the novel Kv7, the seven- eight years of lack of a new branded medication, but now you have one with a really novel mechanism, will really be, I think there'll be a lot of excitement for AZK, particularly as they try to incorporate it with the other kind of standard mechanisms that they currently use.
Yeah, thanks, Darren. Some of the questions have been also just to try to go a little deeper on the comorbid both depression and anxiety. So maybe we just have some questions on the protocol. I'm happy to answer those. And then maybe as we're getting close to the end here, we'll wrap up.
But maybe I'll start, and maybe then you can just provide your perspective because I know your team has been doing a lot on the burden of comorbid depression and then again where you think AZK would fit in into the treatment paradigm as we just think about the profile of the molecule. So in our phase 3 program in X-TOLE2, so we didn't do this in phase 2, but in phase 3, we have exploratory endpoints both on depression and anxiety. These are going to be patient-reported outcomes. But every patient, every visit, we will see how they're doing in terms of depression and anxiety. And we are collecting those data. We didn't do it in phase 2, but we will in phase 3. These are exploratory endpoints. We're not enriching the population for comorbid depression.
So there will be probably a subset of patients that may have maybe impaired at baseline, and we'll take a look at how they're doing over time. So we will collect some information and data from the clinical study, which I think will be informative. But then, Darren, maybe you can just comment on the commercial side and what you're hearing because I know your team's done a lot on this side as well.
Yeah, exactly. And I think every interaction that we have with physicians, the burden of depression and anxiety, it's just overwhelming in this patient population. And when they talk about all the attributes that we've outlined today, to a man and a woman always also say that, boy, if any benefit to even mood- neutral because you have some like levetiracetam that can have a negative impact on mood.
But if you could be mood- neutral or have a slight any type of improvement would just be tremendous for these patients. So yeah, it's something we'll continue to work on. There's no doubt, as I think AES showcased with highlighting one of our publications, that this is a significant unmet need in this patient population.
Great. Thanks, Darren. All right. So we've reached time on today's webinar. No surprise, we have a lot more questions than we had time to get to. So thank you for everyone who has submitted questions, and we're happy to connect with you after the call in the coming days and weeks. So feel free to reach out to us at any time. We do want to thank everyone for tuning in today and hearing our updates coming out of AES. Obviously, the initial commercialization activity is led by Darren and his team.
And we're all ready and prepared for our top-line X-TOLE2 data in early 2026. We look forward to connecting with many of you at J.P. Morgan in early January. And in the meantime, we wish everyone a very happy holiday season. So, Operator, we can now end the call. Thank you, everyone, for joining us.