Xenon Pharmaceuticals Inc.

Thank you for standing by. My name is Rebecca and I'll be your conference operator today. At this time, I would like to welcome everyone to the first quarter 2026 Xenon Pharmaceuticals Earnings Conference Call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, Simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. Thank you. I will now turn the call over to Colleen Alabisco, Senior Vice President of Corporate Affairs at Xenon. Please go ahead.

Good afternoon. Thank you for joining us on our call and webcast to discuss Xenon's first quarter 2026 financial and operating results. Joining me today are Ian Mortimer, President and Chief Executive Officer, Dr. Chris Kenney, Chief Medical Officer, Darren Klein, Chief Commercial Officer, and Tucker Kelly, Chief Financial Officer. After completing our prepared remarks today, we will open the call up for your questions. Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the timing of and potential results from clinical trials, the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market regulatory success, and commercial potential in our partners' product candidates. the strength of our clinical trial designs, our ability to successfully develop and achieve milestones in our clinical development programs, including the anticipated filing of INDs and NDAs, the timing and results of those filings and our interactions with regulators, our ability to successfully obtain regulatory approvals, anticipated timing of top-line data readouts for our clinical trials of a Zet2 calendar and other candidates, and our expectation that we will have sufficient cash to fund operations in 2029. Today's press release summarizing Zenon's first quarter financial results and the accompanying quarter we report on Form 10Q will be made available under the investor section of our website at zenon-pharma.com and filed with the SEC on CDAR+. I'll now turn the call over to Ian.

Thanks, Colleen, and good afternoon to everyone joining us today. We are excited to recap an exceptional quarter for Xenon, where we made tremendous progress toward our goal of becoming a fully integrated neuroscience company, delivering life-changing medicines to patients. In March, we reported results from our Phase 3 XTOL2 study of azetucalner, or AZK, in focal onset seizures that exceeded our expectations. Now, with these positive data in hand, we are focused on our NDA submission to the FDA, expected in the third quarter of 2026, and we also continue to work on increasing AZK awareness and education through our scientific engagement amongst HCPs, as well as our commercial readiness activities. In addition, we continue to broaden the therapeutic opportunities for AZK beyond epilepsy with potential neuropsychiatric indications where we have strong preclinical, clinical, and genetic evidence. Our three phase three depression studies in major depressive disorder and bipolar depression continue to enroll, and we're on track to deliver top-line results from Exnova 2 in the first half of 2027. Successful studies in MDD, BPD, or both would serve to benefit patients and substantially expand the commercial opportunity for AZK. Finally, we remain focused on expanding our pipeline through the advancement of our promising earlier stage ion channel programs with exciting candidates that provide the potential to drive our long-term growth. This includes completion of our first in human studies for XEN1701 targeting NAV1.7 and XEN1120 targeting KV7 later this year with the intent to advance both programs to phase two proof of concept studies in pain. As we continue to execute our clinical programs and prepare for the anticipated approval and launch of AZK, we also continue to prioritize maintaining a strong balance sheet. So today I'm going to focus most of my comments on AZK and epilepsy. And then I'll turn the call over to Chris, Darren, and Tucker. As you all know, in Q1, we announced positive top-line results from the XFOL2 study in focal onset seizures, which exceeded our expectations by surpassing the already strong results from the Phase 2b XFOL study. And to our knowledge, demonstrated the highest placebo-adjusted median percent change in monthly focal seizure frequency ever seen in a pivotal FOS study. Similar to XTOL, we observed a rapid onset of efficacy, strong and dose-dependent responder rates, and a consistent safety and tolerability profile. Following the top-line announcement, we were excited to present the data as a late-breaking oral presentation at the American Academy of Neurology annual meeting in Chicago. Around these two milestones, we have engaged with hundreds of epileptologists and neurologists, and the feedback we've received has been incredibly positive. HCPs are enthusiastic about the magnitude of the efficacy benefits seen in our two randomized trials, the breadth and consistency of our safety and tolerability data, the impressive rates of seizure freedom in the OLE, and the key differentiating attributes of AZK. This includes novel KV7 targeting mechanism of action, no titration, once daily dosing, and no dose adjustments for other ASMs. If approved, this profile would add a meaningful new medicine to their toolkit and provide the opportunity for rational polytherapy. We feel increasingly confident in AZK's potential to become a preferred ASM for the significant number of patients who do not achieve seizure freedom with initial treatment. We are working hard to submit our new drug application to the U.S. Food and Drug Administration in the third quarter of 2026. Our base case assumption is a standard review period followed by DEA scheduling, which would put the anticipated launch timing at the end of 2027 or early 2028. At the same time, we are focused on building out our commercial infrastructure and finalizing our go-to-market strategy. And Darren will speak to this a little bit later on the call. Beyond FOS, we're encouraged by the potential of AZK in primary generalized tonic-clonic seizures, and our phase three EXACT study continues to enroll. Positive results in EXACT would enable us to submit a supplemental NDA for an additional epilepsy indication, which would meaningfully increase our addressable patient population. Outside of epilepsy, we're making good progress enrolling our three ongoing neuropsychiatry studies, ex nova 2 and ex nova 3 in major depressive disorder, and exceed in bipolar depression. There is strong rationale for KV7 openers in depression. Several preclinical and clinical studies, including our own ex-novus study, have shown promising signals of antidepressive effects for the KV7 mechanism. Additionally, in bipolar depression, there are genetic links with KV7, including evidence of KV7 downregulation. We look forward to sharing our first top-line Phase III dataset in MDD in the first half of next year. We also continue to progress our early stage programs, including our first in human studies with XEN 1701 targeting NAV 1.7 and XEN 1120 targeting KV7. These are both compelling targets to treat pain with non-opioid approaches. These programs are exciting as they leverage our deep expertise in ion channel science and the strength of our discovery capabilities and would address large unmet medical needs. Acute and chronic pain affects more people than diabetes, heart disease, and cancer combined, yet effective non-opioid options are scarce. There is a significant opportunity for Xenon to be a leader in unlocking the next generation of pain therapeutics. We're also excited about our early-stage epilepsy programs, including our NAV1.1 program in Dravet syndrome. IND enabling studies are ongoing, and we continue to showcase our encouraging preclinical findings at large congresses. such as the recent AAN meeting. Our collaborators in Neurocrin are also progressing a phase 1B study for MBI921355. This is an investigational selective inhibitor of voltage-gated sodium channels NAV1.2 and NAV1.6, which is being investigated as a potential treatment for certain types of epilepsy. Data from this study are expected next year. Finally, I want to highlight another major accomplishment for Q1. which was the completion of our $747.5 million financing. It significantly extends our cash runway into 2029, allowing us to transition to a commercial stage company and advance our depression and pain programs to key data milestones. So now with that overview, I'll turn it over to Chris to provide an update on our activities at AAN and our broader clinical program.

Chris? Okay, thanks a lot, Ian. It's been a really exciting time at Xenon since we reported our top-line XTOL2 data. As you would imagine, there's a great deal of enthusiasm in the epilepsy community with the prospect of a new anti-seizure medicine that could address many of the gaps in today's treatment paradigm, including the limited number of mechanisms available. With the strong XTOL2 data that exceeded all expectations, coupled with the long-term OLE data showing sustained effects and impressive seizure freedom, I'm incredibly excited about the potential for AZK to positively impact the lives of patients in the near future and for decades to come. Recently, our team spent a week in Chicago at the American Academy of Neurology annual meeting, where we gave several important clinical, preclinical, and real-world data presentations, which collectively underscored the significant opportunity for AZK and our growing leadership within epilepsy. I'll start by highlighting the XTOL2 data that were featured as a late-breaking science presentation. Every year, AAN receives more than 300 late-breaking science submissions, and this year they selected just 18 abstracts for data that they viewed as warranting expedited presentation and publication to their neurologists. Dr. Jackie French of NYU and chair of the XTOL2 Steering Committee presented the XTOL2 data in both an oral platform presentation as well as a poster. The reactions were very positive, with the session moderator from Harvard University and Massachusetts General Hospital characterizing the data as outstanding. And Dr. French highlighting rapid onset of efficacy and no titration as key differentiating aspects of AZK that will appeal to physicians. Our XTOL2 presentation reinforced the positive top-line data we announced in March, including that the study met its primary endpoint of median percent change in monthly FOS frequency from baseline to week 12 in both the 25-milligram and 15-milligram AZK dose groups compared to placebo. Specifically, we observed an MPC reduction of 53.2% for 25 milligrams, 34.5% for 15 milligrams, and 10.4% for placebo, results that were highly statistically significant and actually outperformed the Phase IIb X toll study. We also observed early dose-dependent MPC reductions in weekly FOS from baseline to week one, which were sustained through the double-blind period with both AZK doses. reinforcing AZK's rapid and sustained anti-seizure activity. These efficacy results are even more impressive when you consider that XTOL and XTOL2 included the most treatment-resistant FOS population ever trialed. At baseline, patients in XTOL2 were experiencing a median of 13 seizures per month, had been treated with a median of five prior ASMs, and more than half were already using three concomitant anti-seizure medications. About 60% were on or had already tried and stopped Sinovimate, and still, they had not achieved seizure control. We also provided additional data from our responder rate analysis, where we observed dose-dependent increases in the proportion of participants with at least 75% and 90% reductions in monthly seizure frequency through the double-blind period. We also presented 100% responder rate data, which demonstrated that a 100% reduction in seizures over the double-blind period was attained by a greater proportion of participants with AZK 25 milligrams than placebo, results which were highly consistent with the results of XTOL. While AZK has a rapid onset of efficacy, it also takes a few weeks to reach steady state levels. And we've seen in other instances, such as the XTOL-OLE, that efficacy continues to build over time. Therefore, we also conducted a postdoc analysis of the XTOL-2 data to see if a greater proportion of participants experienced a 100% reduction in seizures over time. Indeed, 100% responder rate increased steadily over the last eight, six, and four weeks. For example, the 100% responder rate over the 12-week double-blind period for 25 milligrams was 6.5%, but over the last six weeks, it increased to 11.3%, and over the last four weeks, it increased further to 13.7%. We're looking forward to continuing to follow this trend in the Phase III OLE. This brings me to our other key AZK presentation at AAN, our 48-month XTOL OLE data. where the trend of efficacy building over time is even more compelling. The OLE is also where we are best positioned to evaluate whether patients are truly achieving seizure freedom, which has been a consensus definition of no seizures for 12 months or more. This definition also aligns to practical, real-world outcomes for patients. As in many states, 12 months without seizures means they're able to drive again. Our long-term OLE data demonstrated continued reductions in focal seizures with a 91% reduction in monthly seizure frequency for those treated for at least 48 months. Those who entered the study taking one or two ASMs demonstrated a 100% reduction in monthly seizure frequency compared with an 82% reduction in seizure frequency among those taking three ASMs at baseline. With regards to seizure freedom, the patients treated for at least 48 months, almost 40% were seizure-free for at least 12 months, and one in four were seizure-free for at least two years. If you consider how treatment-resistant the overall patient population was at baseline, this is truly remarkable. Based on feedback from our investigators, we understand some of these patients have never experienced seizure freedom before taking AZK. and their stories fuel our desire to bring AZK to patients and clinicians as quickly as possible. Finally, I'll also note that our AZK data at AAN continue to support a general, well-tolerable profile. The safety data are remarkably consistent between XTOL and XTOL2 in terms of types of treatment emergent adverse events, the frequency at which they occurred, the number and types of serious adverse events, and the events that led to discontinuations. The most common treatment emergent adverse events across both studies in the AZK dose groups were dizziness, somnolence, headache, and fatigue. With more than 800 patient years of safety and exposure data, we are comfortable that this profile is consistent with other well-tolerated ASMs and with a drug that is potent and active in the central nervous system. We will continue to add to these robust safety and tolerability data with our ongoing Phase II and Phase III OLEs in epilepsy. Another focus for Xenon at AAN was education around unmet needs in epilepsy care, including the impact that titration has on both patients and HCPs, and the opportunity for no-titration options to improve treatment experiences, outcomes, and healthcare resource utilizations. We presented real-world data that captured the challenges reported by patients around medication schedules, daily life, and quality of life during titration periods, while physicians reported challenges related to treatment complexity and cross-titration. When questioned on their perceptions of ASMs without titration, most patients noted that they either agree or strongly agree. that initiating an ASM without needing to titrate to a stable dose would boost their confidence, reduce anxiety, and improve adherence. Physicians noted that no titration options would increase simplicity as many patients are already on complex drug regimens. These findings suggest using ASMs that do not require titration may reduce stress and simplify FOS management. And we heard this echoed in our discussions at AAN as well, especially for general neurologists who value ease-of-use attributes in prescribing decisions. We rounded out our AAN scientific program with an oral presentation of preclinical data from our NAV1.1 program in Dravet syndrome. These data demonstrated that selective potentiation of NAV1.1 channels in Dravet mice improved motor function suppressed spontaneous seizures, prevented sudden unexpected death from epilepsy, increased long-term potentiation, which is a potential cellular correlate of learning and memory, and produced more mature dendritic spine morphology. The data continued to support our belief that targeting NAV1.1 with a small molecule could potentially address the underlying cause and symptoms of DRAV-A syndrome. IND enabling studies for this program are currently ongoing. All in all, we're very proud of our scientific contributions at AAN, as well as how positively they were received by the community. Moving on to our other clinical programs, we've had a lot of activity as we continue to enroll three phase three studies in depression and two phase one programs in pain. Depression is an area where the differentiated profile of AZK including its novel mechanism of action, rapid onset of action, and potential benefits on anhedonia, could meaningfully benefit patients. Like epilepsy, the depression landscape has experienced a dearth in innovation for some time, and new mechanisms are urgently needed. Our clinical development team has made great progress with Exnova 2 and Exnova 3, which are ongoing and enrolling patients with major depressive As Ian previously stated, we anticipate sharing top-line data from Exnova 2 in the first half of 2027. In addition, EXCEED, a Phase III clinical study evaluating AZK in patients with bipolar I and bipolar II depression, also continues to enroll. This is another area where there is significant unmet need for safe and effective therapies due to non-adherence related to side effects and other factors. The physicians that we've spoken with are keenly interested in AZK's novel selective KV7 mechanism of action, potential benefit on anhedonia, rapidity of onset, and differentiated safety profile. To round out my remarks, pain continues to be an area of growing focus, and we're looking forward to completing our first in human studies for our novel pain programs this year. There remains a strong desire for non-opioid pain therapies, given the limited efficacy of current options and substantial risk of abuse and dependency tied to opioids. We know that analgesics can act along multiple different points of the pain pathway and interrupt the pain signal on its way to the brain, and we believe in the potential for NAV1.7 inhibitors and KB7 potentiators to play important roles at multiple points in this pathway, including in the initial transduction of pain stimuli into pain signals, the transmission of those pain signals along nociceptive neurons, and the relay from peripheral sensory neurons to spinal cord neurons in the central nervous system. We believe NAV1.7 is the best genetically validated pain target with striking genetic data in patients with loss of function mutations that have no ability to feel pain. Gain-of-function mutations have also been identified that drive pain disorders, further underscoring the critical role NAV1.7 plays in pain signaling. With XEN1701, as well as other Xenon programs in preclinical development, we believe we have solved for some of the critical limitations of prior NAV1.7 compounds. KB7 is also a compelling pain target to modulate neuronal hyperexcitability at multiple points along the pain pathway, and we believe KB7 potentiators have the potential to treat a range of pain conditions. This is supported by high levels of KB7 expression throughout the pain pathway, and our preclinical data shows that KB7 is enriched in the C and A delta subtypes of sensory neurons. In addition, KV7 openers can block action potential firing in both DRG and spinal cord neurons, thereby significantly inhibiting pain signals from reaching the brain. Evidence supports that dysfunction or downregulation of KV7 activity has been observed in altered pain states. We're excited to be advancing an optimized KV7 opener with our XEM 1120 program. We're really encouraged by our NAV 1.7 and KD7 work in pain and look forward to providing more details later in the year. With that, I'll turn it over to Darren to provide an update on our path to commercialization, including interactions and discussions at AAN. Darren.

Thank you, Chris. I would like to reinforce the comments from Ian and Chris regarding the strong interest in our XTOL2 data since we first reported the results in early March. Since then, we have seen sustained engagement and interest from a broad group of epileptologists and neurologists attending AAN. Across these interactions, they reiterated the strength of our XTOL2 and OLE datasets and AZK's differentiated profile, and we consistently heard enthusiasm about the potential to use AZK in clinical practice. Physicians highlighted the importance of efficacious therapies that are also straightforward to incorporate into routine patient care. AZK's unique mechanism and its expected profile of once daily dosing, an effective starting dose, no drug interactions, and no dose adjustments with other ASMs remains among the most frequently cited and most compelling attributes. Looking ahead, we plan to increase our understanding through primary research, advisory boards, and one-on-one meetings as we continue to deepen our insight of AZK in advance of potential approval and launch. Based on our growing engagements with this audience, we believe AZK has the potential to become the preferred branded ASM for general neurologists. We also continue to hear that AZK's profile may support greater confidence in treating a broader range of epilepsy patients within community practices. rather than referring patients to a level three or four epilepsy center after exhausting existing available options, which could contribute to broader adoption, improved patient outcomes, and meaningful prescription growth over time. Launch readiness remains a key enterprise priority. Over the past several months, we have focused on increasing our scientific engagement with epilepsy specialists, neurologists, and advanced practice providers, while continuing to expand our field-based capabilities. including the recent addition of several medical science liaisons. In parallel, we have initiated discussions with payers to introduce Xenon, better understand unmet needs, and communicate potential value proposition of AZK. In March, we attended the Pharmaceutical Care Management Association, or PCMA, meeting for the first time and held a number of productive introductory discussions with pharmacy benefit managers and payers. The timing of these conversations alongside our XTOL2 data release helped drive interest and momentum. We plan to participate in several national payer meetings this year, and in the coming months, we expect to expand our field-based payer team to continue dialogue with this important constituency and further strengthen our launch preparedness. As we execute on these launch readiness priorities, we remain focused on building an experienced launch and lifecycle management organization. advancing innovation across channels and patient services, and increasing awareness across our customer universe. Our commercial objective is to establish Xenon as a leader in epilepsy, and we believe we are making meaningful progress towards that goal. We are highly motivated by the opportunity to deliver meaningful benefits to patients and the physicians who care for them. With that, I'll turn the call over to Tucker to review our financial results.

Thanks, Aaron. As Ian mentioned, the exceptional results in XL2 allowed us to complete a highly successful public offering of nearly $750 million, which fortified our balance sheet as we moved toward potential approval and launch. We ended Q1 with cash, cash equivalents, and marketable securities of $1.3 billion, compared to $586 million as of December 31st, which, based on our current operating plans, provides cash to fund operations into 2029. Given our strong balance sheet and fiscal management, we are well positioned to support AZK's U.S. launch, multiple registrational programs for AZK, and the continued maturation of our early-stage pipeline. I would refer you to our press release and our 10Q filed today for further details on our financial results. Overall, it was a very exciting time at Xenon as we continued to build momentum in our pipeline spanning epilepsy, depression, and pain, and make progress against our critical priorities, with our first priority being the submission of our NDA for AZK to the FDA in the third quarter of 2026, as well as the advancement of our commercial readiness activities support a strong launch in FOS. We also remain focused on broadening the therapeutic opportunities for ACK beyond epilepsy, and we continue to make good progress in rolling our studies in major depressive disorder and bipolar depression, with the readout of our first depression study anticipated in the first half of 2027. And lastly, we are pleased with the momentum in our early stage pain programs, and we anticipate completing the first in human studies for 1701, targeting NAV 1.7, and 1120 targeting KV7 later this year. And we seek to advance both programs to phase two proof of concept settings. We are in an excellent position to execute our priorities due to our strong cash position, and we are feeling very optimistic about a bright future as we begin to transition to a commercial stage company, delivering meaningful medicines to patients. And with that, we can open the call up for questions. Operator?

At this time, I would like to remind everyone in order to ask a question, Press star then the number one on your telephone keypad. We'll pause for just a moment to compile the Q&A roster. And your first question comes from the line of Paul Matias with Stifle. Your line is open.

Great. Thanks very much. Congratulations on everything from the first quarter. I wanted to ask a couple questions on the pain programs, if that's okay. First, as it relates to the NAV 1.7 compound, I was wondering if you could talk about where you've gotten to in your Phase 1 program at this point and how much you feel like you've de-risked some of the safety issues that have plagued other drugs. And then separately, can you maybe just speak to more specifics around these Phase 2 plans specifically? and acute pain and, you know, what would sort of the size and scope of those studies potentially look like, assuming the phase one data later this year lets you advance? Thank you.

Thanks, Paul. Chris, I'm happy to start and then provide your perspective, especially on the future clinical development. So, Paul, we announced at J.P. Morgan earlier this year in January, I think, some of the progress we had made on both NAV 1.7 and KV7. You asked specifically around NAV 1.7. At that time, you know, we said that we already felt that we were at high enough exposures to get receptor occupancy that would mimic the human genetics. So we had already made good progress in those early cohorts of dose escalation. If we kind of bring forward to today, we've continued to enroll additional healthy volunteers in that phase one study. So I think sitting today, we feel really good that we can safely dose, have the appropriate therapeutic index, and give this mechanism a real shot to show proof of concept data in phase two. So based on what we know today, our plans are to move forward into a phase two acute pain proof of concept study. I can start on how we're thinking about it, and then Chris can add some details. Obviously, on the acute pain side, we're looking at studies like bunionectomy or abdominoplasty. We haven't yet fully designed the studies. We would want to have them of sufficient size and power. obviously to show, and these would be placebo-controlled studies, to show a difference between active and placebo. The question really that we continue to think about internally is just how many arms, active comparators, how many doses, all of those things we're still planning. And that'll become clearer as we finish phase one and we have a really good idea of what we're seeing in terms of the dose response and safety profile in those phase one healthy volunteer studies. Chris, any color to add on additional details for future development?

No, I'll just double down on your point that we think we have what we need to go forward into phase two on both programs. And we haven't worked out exactly what the plan would be after the proof of concept that would be with abdominoplasty and or bunionectomy.

All right, all good. Thank you guys very much. Thank you.

Your next question comes from the line of Tess Romero with JP Morgan. Your line is open.

Hey, guys. Thanks so much for taking our question, and congratulations from us on all the progress. Ian, Chris, I was wondering if tonight you could provide your perspective on the How the seizure freedom data that you have shared at 12 weeks from XTOL2 compares to what we know about XCOPRI on a cross-trial basis numbers-wise? You know, how do you think doctors will approach thinking through the seizure freedom data that we have for these two assets, given that nearly 60% of the patient population were taking or had already discontinued XCOPRI and XTOL2, and of course that XCOPRI has to be titrated? Thank you.

Thanks, Tess.

I'll start. Chris can provide his perspective, but I also want Darren to weigh in because we've had a huge amount of interaction with HCPs and the feedback that they're providing us. You know, and Chris touched upon some of this in the prepared remarks, but maybe I'll give a little bit more detail. So Chris mentioned in the prepared remarks that the consensus definition of seizure freedom is really having no seizure for 12 months. And so when we talk about our seizure freedom data with prescribers, we focus more on our open label data than our double blind data. So you'll hear us use terms like RR100 in the double-blind period, which is the percentage, you know, those patients, percentage of those patients that had 100% reduction over the double-blind. You've asked for a comparison between ezetucalner and Sinovumate. You know, it is a cross-trial comparison and it is challenging, but I will make a couple of comments. One, it was a materially different patient population. So Chris walked you through and you've seen in our publications and our posters and in our disclosure that we believe that both in XTOL and XTOL2, this was the most refractory population ever trialed in a pivotal FOS study. And when we look at the Sonobamate data and the double-blind data trials that they did over a decade ago, this was a significantly less refractory population. So we are comparing actually two different clinical populations within FOS. You also mentioned another key factor, which is because Sinovamed is titrated, when they look at their RR100 during their double blind, they only report over the maintenance period, which is the last six weeks of dosing. One of the reasons why we had a breakdown of that last eight, six, and four weeks. Maybe the last comment on the cross-trial comparison is that, you know, often they show their data at their 400 milligram dose which the feedback we get, and we see it, you know, both in data, but also in feedback from prescribers, is that patients rarely get to 400 milligrams. So if you look at their 200 milligram dose, and you look at the last period within our double-blind period, you know, within the last six weeks or four weeks of our data, I would actually say that our RR100 is higher than the Sonobamate data seen at their 200 milligram dose. Then the last point you made, which I think is an important one, is we actually have a synovomate refractory population in our trial. When, as we mentioned, about close to 40% of patients were on background synovomate and approximately another 20% of patients had tried it and had failed it either for efficacy or tolerability and were no longer on the drug. So overall, I wanted to provide a little bit more of that background because I think our data stack up really well, and I haven't even talked about the open label data. That's just a cross-trial comparison during the double-blind period. So I'll pass it to Chris to talk about the open label seizure freedom data, and then to Darren on how that's really being pulled through into the real world.

Yeah, thanks a lot, Ian, and thanks for the question, Tess. I mean, it's interesting, you know, in the epilepsy field, I think there's a little bit of a disconnect. And what I mean by that is that if you talk to epileptologists and neurologists and you ask them what they're hoping to achieve, they talk about seizure freedom on a long time horizon, like at least six months, more like a year, sometimes more. And yet in the same conversation, they'll ask, what was your seizure freedom over a month or two or three months? And so there's this sort of inconsistency there that I just want to kind of note. I think that as you make the comparisons, Ian's already commented on, you know, the details matter here. If you're talking about seizure freedom with Sinovumate at 400 milligrams with hardly anybody taking 400 milligrams, and really it's, you know, 40% of patients are are treated with Sinovumate at 200 milligrams and the rest of them are treated at lower doses. I think it's important to think about dose. Also, you know, in the label, when they talk about seizure freedom and Sinovumate, they're excluding the first six months, excuse me, six weeks of the trial period, which is why we've provided sort of these different cuts of seizure freedom to allow a better comparison. But I mean, let me just zoom out for a second. I was prescribing when levotirazetam, Keppra was approved. And what people want, especially general neurologists, is something easy to use. And with the ZetuCounter, you don't have to worry about titration. You don't have to worry about drug-drug interactions and manipulating other medications to get a therapeutic dose and so forth. So it's easy to use. But then just to kind of wrap it up with the seizure freedom, I mean, I really think that we should be talking about what's happening in the long term. And what we're seeing in the long term with the data that we just presented at AAN is that of the patients who've been treated for four years or more, we're seeing 40% of patients with seizure freedom for a year or more. That's what really matters, not so much what happened over one month or two months. Thanks, Tess. Darren?

Thanks, Chris, and maybe Darren can weigh in here as well. Yeah, thanks, Tess. You know, I just reiterate what Ian and Chris said. When we engage with physicians, both epileptologists and general neurologists at AAN and other forums, you know, this is largely is an epileptologist drug. And when we query about the seizure freedom as it relates to the 400 milligram, I'll just put a finer point on what Ian and Chris said. Very, very few, if any, patients get to the 400 milligram dose. So as it relates to their own experience with the seizure freedom, it's not as compelling as in the real world. Now, Excoprid does have benefit, but they're not seeing anywhere near what they see at the 400 milligram. And I make this comment about it being an epileptologist drug, because when we talk to general neurologists, they have really struggled with using it. And they're pretty much, they try it once and they're done. And this is, as what Chris said, what differentiates AZK and what we believe will make this a tremendous opportunity is with the general neurologist. The ease of use attributes, the lack of titrations, daily dosing, and no DDIs really, really ring true with them.

And they look forward to incorporating in their practice. Thank you, Tess.

Your next question comes from the line of Corey Kasimov with Evercore. Your line is open.

Hi, this is Addy on for Corey. Just on the earlier question asked on the paying assets, I just wanted to ask, that can you confirm if investors should anticipate any data this year? I believe earlier it was mentioned that maybe phase one sad mad data might be presented. I just wanted to get if we should anticipate that data.

Thank you. Thanks, Adi. Yeah, we're very comfortable in saying that the phase one healthy volunteer studies for both 1701 and 1120 will complete this year. So in terms of how much of those data we provide publicly for competitive reasons, I think, you know, obviously we'll talk about that we believe we have enough receptor occupancy and exposure and coverage to have a really good shot at seeing an analgesic effect in a proof of concept study. But really to be determined right now whether we're going to broadly show the phase one data publicly, but we are comfortable that those studies will wrap up this year.

Your next question.

Operator, we can move to the next question.

Your next question comes from the line of Peyton Bonsack with TD Cowell. Your line is open.

Peyton Bonsack Hi, guys. This is Peyton on for Joe, and thanks for taking our questions. I guess, have you scheduled or had a pre-MDA meeting yet? And if you have had the meeting, can you talk about any feedback you've received from the FDA? And then I guess the DE schedule, can you walk us through the timelines and your expectations for what kind of schedule you would have for that?

Thanks. Chris, do you want to address the regulatory interaction?

Yeah, sure. So just the second part of that was the timeline on that meeting. Was it just a reiteration of the other part of the question or was there something different there?

I was more referring to the DEA scheduling and the actual timelines should you get approved.

DEA scheduling.

Yeah. Okay. Yeah. So what we're sharing is that what we've guided on, we just had top line XTOL 2 in March. We've guided that We're expecting about a six-month period of time between that and submitting the NDA. We're expecting a standard review of 12 months, and then DEA scheduling is expected to be three months, which is why Ian stated in his comments that we expect approval end of 2027 or early 2028. You know, we have, obviously, I mean, pre-NDA meetings are standard. We're expecting for that to occur. in between the top line data, which has already occurred in the NDA submission, obviously, in the fall. But we haven't gone into specifics about when exactly that's going to take place. I will tell you that we've had thoughtful and timely interactions with FDA. And we think we have a decent reputation with them. And we haven't foreseen any problems up till at this point in time.

So we're looking forward to more interactions with them in the future. Great, thank you.

Your next question comes from the line of Andrew Tsai with Jefferies. Your line is open.

Hey, good afternoon. Thanks for taking my questions. This is Matt Barkas on for Andrew Tsai. I just wanted to see if you can give us a little bit of flavor on what other Phase III data analysis that you might share later this year, especially at AES conference in December, which can further showcase ACK's potential differentiation.

Thanks, Matt.

Chris, do you want to walk through maybe some of our thinking around AES and additional analysis?

Yeah. So we've, as you can imagine, we've spent a lot of time trying to understand what's going on with the phase three and understanding all the data. And so we're sort of working through exactly what we intend to submit as potential abstracts at AES. As you know, you submit those and they may or may not be approved. We've had a pretty good acceptance rate, but you don't know for sure. We're focusing on looking at kind of the combination. Now we have two, what we consider two pivotal trials for FOS. And so we're interested in kind of combining that data and sharing with the world what that efficacy and safety data looks like combined. We're also, you may remember from the XTOL study that we looked at seizure subtypes And so we're probably likely to look into that and share that. And then, of course, every year we update the XTOL OLE data. And so those are the things that for sure will happen. And then we're just kind of working through whether there'll be anything else there.

Ian, do you want to add anything to that? No, that was great. Thanks, Chris.

Your next question comes from the line of Brian Scorny with Baird. Your line is open.

Hey, guys. Thanks for taking the question. This is Charlie on for Brian. So just thinking about your NAV 1.1 in Dravet, obviously a pretty crowded space. How do you see this compound and mechanism differentiating from the field, especially considering there are some other therapies out there addressing this issue in epilepsy. And just one more, if I could ask on pain, what are you thinking about long-term in terms of chronic pain versus acute pain and how each asset might fit into that paradigm?

Thank you. Thanks.

Chris, I can start on NAV 1.1 and then feel free to add, and then we can talk about the the pain, although we talked about earlier that, you know, we're still working on kind of the development strategy for the pain assets. On NAV1.1, so these children that have Dravet syndrome are haploinsufficient for NAV1.1, so they have 50% of the protein. The drugs that are currently approved address the seizures. So drugs that are used like Clobizam or Epidiolex or Fentepla, are really trying to prevent the seizures that these children are having. Really where we believe the field is going in addition to those therapies is to see if we can start to correct the underlying genetics. And so there's ASO approaches that I'm sure you're aware of. And what we think is the opportunity to have a small molecule that can be orally administered and can really be titrated or appropriate weight-based dosing for these patients that have a wide variety of weights as they're diagnosed generally within the first six to 18 months of life. And so if there's an opportunity to have an oral small molecule where we potentiate the channel so we can increase current through the wild type channel as the opportunity potentially to correct the underlying challenges of this disease, And the preclinical data that Chris walked through and you've seen in poster presentations, and we had an oral presentation, standing room only oral presentation at AAN this year, those data are quite remarkable. And these are in genetic animals. So these are in animals that are haploid sufficient and very much look like the human phenotype in terms of the spontaneous seizures and the SUDEP. And not only is the seizure reduction significant, impressive in our preclinical studies, but also really the potential for disease modification. You know, we're protecting these animals from death and really helping them in terms of the long-term potentiation. So we've showed some of those data historically. I think they're really interesting. We're now in tox studies, but I think there's a huge opportunity and need for better therapies for Dravet, and I think this will fit in really nicely, but it's early days. Chris, anything to add on the 1.1, or do you want to move to just thinking about longer-term development in the pain portfolio?

A couple of things. Thanks, Ian. Maybe slightly crowded, but if you think about, you know, this is a really devastating disorder, and so I think it's good that multiple people are working on this. The reason why we think we're differentiated is because we're coming along with a small molecule that we think will will deal with the underlying pathophysiologies in a similar manner to what Stokes ASO is doing. But obviously an ASO is being delivered through the intrathecal route, and this would be an oral therapy. So I would just draw kind of an analogy with what happened in spinal muscular atrophy where gene therapy came along, ASOs came along, and then oral therapies came along and how that went. So we do think that we have something to offer these patients. And then, yeah, we're still working through the pain. So we're focused on getting out of first in human, interprover concepts, and then we still need to figure out chronic versus acute and all sorts of different things in the coming months and weeks.

And maybe I can just add on the pain side, obviously the first proof of concept studies will be in acute pain, and we've talked about bunionectomy or abdominoplasty. There's nothing in the underlying genetics in NAV1.7 or the mechanism of KV7 that should suggest or support that these mechanisms should only work in acute chronic pain. or nociceptive or neuropathic pain. So, you know, if these programs continue to look promising and we can get good proof of concept, the plan would be to go quite broad in terms of the life stage clinical development.

Great. Thank you for all the call that are really helpful.

Your next question comes from the line of Miles Minter with William Blair. Your line is open.

Thanks for taking the question. One on the commercial side, I find it interesting that we're all comparing Excopri when that's not the number one branded product, Priviact is, and I think that that had gone generic at the start of the year. So the question is, is that a headwind to marketing of a newly branded ASM there because costs are coming down in the general neurology practice? Or is that actually a tailwind because you no longer have to compete for that branded slot against Brutvia actually kind of coming in and taking the market specifically within that general neurologist population? Thanks.

Thanks, Miles, for the question. No, I think on the contrary. I think when you look at AZK, all the attributes, particularly the novel mechanism after generations of SV2A channel blockers, sodium, sodium channel blockers, SP2As, and GABA, you know, the novel KV7 is a benefit. All our ease of use attributes that we've outlined on the call and that we get positive feedback from both epileptologists and general neurologists. And you look at the timing of when we ultimately launch, it'll be almost a decade of really what I would characterize as, you know, kind of a stagnation of development and focal epilepsy. And so we really think that's the backdrop along with our clinical data and profile, that we can really, really have a great opportunity here. And again, I think if you look at the case with XCOPER, we've talked about that, but even I think Briviac, it was another kind of me-too mechanism on top of a wildly successful parent in Kepra. And so I think that's a completely different market and opportunity than what we have with AZK as we look in the future and we prepare to launch this.

Your next question comes from David Hong with Deutsche Bank. Your line is open.

Hi there. Thanks for taking my questions. So maybe first, again, on the commercial side, given the strong balance sheet you have now, how can you think about leveraging that to perhaps ensure the best commercial launch you can for AZK and focal epilepsy? For example, would you think about maybe increasing the number of sales reps that you would field And then just thinking about different, you know, different angles out there in the focal epilepsy market, a competitor of yours is doing a monotherapy study, I believe. And they think that, you know, by weaning patients off background meds and having them on a monotherapy, that may be able to allow them to get into earlier lines of treatment. Was curious if you've ever thought of a study design like that and if you think that would be helpful for AVK. Thanks a lot.

Thanks, David. I'm happy to start just because I think a little bit of historical context is important here. And then Darren will go through kind of the details of preparing for launch. And then, Chris, do you want to address the question just on monotherapy and the label, at least how we think about that? Really, since the XTOL data in 2021, David, we have really moved to investing in commercial preparation at risk. I think this is a generational type opportunity, paradigm shifting. As Darren mentioned, it'll be almost a decade since we've seen a branded launch in FOS. but it's been ages since we've seen this kind of mechanistic diversity and the profile of something like is that to calendar is that to calendar so given our confidence going into the phase three route phase three readout next tool two we started that commercial preparation already so not only you know was darren hired almost a year ago but we've had field medical out um msl speaking with prescribers and engaging in medical and scientific exchange This summer, it'll be two years since we've had that team out there. Darren's already got his leadership team in place. We've had people on the access side in place for years. So we've really believed that early investment was going to be an opportunity here to have real success in those early days of commercialization. But Darren can give you a little bit more detail on that.

Yeah, I think, thanks for the question. And, you know, if you kind of, and Ian hit it on it, you look at successful launches and and some of that I've been a part of, there's a few ingredients. One is the early investment, which I was very pleased joining Xenon that was in place. Second is the team that you can put yourself, put together. And I think from a commercial leadership perspective, we have folks with deep epilepsy experiences and relationships, launch experience, which provide us, I think, a leg up. Third, and also part of that is we will be a variable desirable place for professionals that have dedicated their careers to epilepsy. As we pointed out, there's been really nothing new. And so I think when we start posting positions, we're gonna get the best available people. Then you turn to the product that we have available to us. And from a brand marketing positioning perspective, the clinical data is somewhat argue the best in focal seizure. I think as we think about the opportunity to price this and extract the value that we think that the asset deserves, And then also, too, the services, the distribution model, I think we're thinking of it in a very creative way that, again, will extract the most value, but most importantly, have the best patient and physician experience. Because as we know, while it takes a lot of effort and investment to create the demand, converting that prescription to paid scripts and persistency and compliance is That's the entire equation. And so when we think about our commercial team and our launch preparation, all those variables are being put in place. And again, with the backdrop of the clinical profile that we have with ACK, we're extremely, extremely excited and bullish on this launch. And Chris, you want to talk on the monotherapy?

Yeah. I mean, it's hard to not be blunt. I don't see the upside of doing it, frankly. So from a labeling perspective, the current labels don't say that these drugs are approved for adjunctive. They just say that they're approved for the indication. So I don't see any upside from a labeling perspective, per se. I'll defer to Darren on the commercial side. I will say this, though. If for whatever reason I did see an upside with doing a monotherapy study, I would do a monotherapy study for drug versus placebo from the very beginning. I think if you're If you're manipulating other ASMs and trying to back off and then interpret that efficacy and safety data, it's probably very challenging.

Thanks, David.

Your next question comes from the line of Ben Burnett with Wells Fargo. Your line is open.

Hi, Tim. This is Orpheus on for Ben. Good afternoon. How's all the progress? Maybe just a quick one on our end. As we look forward to XTOL3 data and a potential XUS launch, how are you thinking about commercialization in XUS territories? I know that in the past you have shared you would look to partner in such geographies, so is this still your latest thinking, and are there any updates you can share on that front? Thank you.

Sure. I'm happy to address that. So we are doing the clinical development that we think will meet regulatory requirements around the world. So we've been talking for some time that the clinical program should meet requirements in Europe. And then an update over the last couple of quarters for us was interaction with PMDA and the incorporation of Japanese sites and subjects into XTOL3 to meet the requirements in Japan without having to run a completely separate phase three program in Japan. So I think we've done everything kind of across the board to continue to drive the global clinical development and drive value. We've also been really clear that we're not going to build infrastructure, market access and commercial infrastructure outside of the US. And so when the appropriate time is right, that would be when we would engage with potential partners to access those markets. But right now, we're really focused on the global clinical development.

Very helpful. Thank you very much.

I will now turn the call back over to Ian Mortimer for closing remarks.

Thanks very much, operator, and thanks to everyone for joining us today. I know there were other questions in the queue, so if we didn't get to your question, we will reach out to you directly to connect. And we look forward to providing continued updates as we advance our programs and we deliver on important milestones throughout the remainder of the year. So, operator, we can now end the call.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.