Q2 2025 Xenon Pharmaceuticals Inc Earnings Call

Speaker #3: Thank you for standing by. At this time, I would like to welcome everyone to Xenon Pharmaceuticals' second quarter 2025 earnings conference call. All lines have been placed on mute to prevent any background noise.

Speaker #3: After the speakers' 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.

Speaker #3: I will now turn the conference over to Chad Fugere. You may begin.

Speaker #4: Good afternoon. Thank you for joining us in our call on the webcast to discuss Xenon's second quarter 2025 financial and operating results. Joining me are Ian Mortimer, Xenon's president and chief executive officer, Dr. Chris Kenney, Xenon's chief medical officer, and Darren Klein, Xenon's chief commercial officer.

Speaker #4: After completing their 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.

Speaker #4: The potential efficacy and safety profile, future development plans, and current and anticipated indications addressable market, regulatory success, and commercial potential of our and our partners' product candidates.

Speaker #4: The efficacy 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.

Speaker #4: The timing and results of those filings, our interactions with the regulators, and our ability to successfully obtain regulatory approvals. The anticipated timing of the top-line data readout for our clinical trial that is at your counter, and our expectation that we will have sufficient cash to fund operations in 2027.

Speaker #4: Today's press release summarizing Xenon's second quarter financial results and the accompanying quarterly report on Form 10-Q will be made available under the Investors section of our website at xenon-pharma.com.

Speaker #4: And filed with the FCC and on Cedar Plus. Now, I would like to turn the call over to Ian.

Speaker #5: Thank you, Chad, and good noon, everyone, and thanks for joining our call today. We are excited to share a number of advancements across our pipeline as we have made significant progress over the past quarter.

Speaker #5: As we reflect on the first half of 2025, we continue to advance against our key strategic priorities. Number one, driving towards phase three data, NDA submission, and commercializing as at your counter for the treatment of focal onset seizures in US, number two, broadening the as at your counter opportunity across additional epilepsy and neuropsychiatric indications, and number three, expanding our product portfolio through the advancement of our promising earlier stage IN channel programs.

Speaker #5: Today, we will cover details and milestones relating to these exciting program advancements and momentum we have going into the second half of 2025. I will begin with a brief review of highlights from this past quarter, starting with our most advanced Phase 3 clinical trial, XTOL-2.

Speaker #5: As disclosed in today's press release, we have completed patient recruitment in XTOL-2. This is a significant milestone in the development of as at your counter, and keeps us tracking to report top-line results early in 2026.

Speaker #5: In anticipation for our first approval and commercial product as a company. We plan to refine our guidance for the timing of top-line results after last patients are randomized.

Speaker #5: We remain highly encouraged by the potential of as at your counter to deliver on the promise of a new anti-seizure medication with a entiated product profile to what is available today.

Speaker #5: And this could benefit people living with a debilitating effects of uncontrolled seizures. From the outset, we have prioritized working with high-quality, experienced sites to maximize study success while diligently monitoring key metrics throughout the study.

Speaker #5: As discussed on previous calls, we are pleased that these metrics align consistently with our successful XTOL study, and continue to have confidence in XTOL-2 and share the epilepsy community's excitement as we progress towards phase three readout.

Speaker #5: It's this excitement that drives our scientific leadership and investment in the KV7 landscape. As at your counter, we have the only KV7 channel opener and the only ASM in development that is backed by long-term efficacy and safety data from clinical studies of patients living with epilepsy.

Speaker #5: Having demonstrated highly compelling placebo-adjusted efficacy in focal onset seizure patients in our Phase 2B trial, durable and sustained efficacy over time through our open-label extension study, and approximately 800 patient-years of exposure and safety data.

Speaker #5: There remains a substantial need for new, efficacious, and well-tolerated epilepsy therapies. Especially for those patients who continue to experience the debilitating impacts of focal seizures even while taking multiple anti-seizure medications, and we believe that as at your counter's key attributes as seen to date, demonstrate its potential to provide an important new option for the epilepsy community.

Speaker #5: We consistently hear positive feedback and excitement within the medical community about as at your counter's compelling value proposition, which includes a novel mechanism, rapid onset of effect, robust efficacy, and multiple ease of use attributes, including once daily dosing, no required titration, along with a ential mood efit.

Speaker #5: As at your counter has the potential to be a best-in-class anti-seizure medication that offers significant and meaningful benefits in the future treatment of epilepsy.

Speaker #5: Chris will touch on more detail shortly, as to our continued work with investigators and the anticipation building in the field. In addition, we believe there is potential for us at your counter beyond epilepsy.

Speaker #5: With initial focus on depression, within our phase three MDD program, we have now initiated Xnova-3, which is the second of three planned studies of as at your counter in major depressive disorder.

Speaker #5: Also during the quarter, we initiated the first of two planned Phase 3 studies in bipolar depression one and two, called the XSEED study. We continue to execute as planned to expand the clinical development of as yet uncovered indications and invest in our neuropsychiatric programs.

Speaker #5: This is a good time to turn the call over to Chris, who will share more details on our late-stage clinical development programs. I'll then provide an overview of our early-stage pipeline programs as well as conclude with a summary of key milestones ahead.

Speaker #5: Chris, over to you.

Speaker #6: Yes. Thanks a lot, Ian. Starting with our phase three epilepsy program, which includes our two studies in focal onset seizures or FOS, XTOL-2 and XTOL-3, and our exact study in primary generalized tonic-clonic seizures or PGTCS, I'm redibly excited to confirm that our phase three XTOL-2 clinical study of as at your counter in FOS has now completed patient recruitment.

Speaker #6: And as guided previously, we expect top-line data in early 2026. This milestone reflects tremendous focus and execution by our clinical operations, clinical development, and field-based medical teams, as well as strong commitment from the epilepsy patient community, our investigators, and their site staff.

Speaker #6: As we progress closer to a top-line data readout, we continue our ongoing educational and scientific outreach efforts to raise the profile as at your counter amongst healthcare providers.

Speaker #6: Our team will have a strong presence at the upcoming 36th International Epilepsy Congress (IEC), taking place August 30th to September 3rd in Lisbon, Portugal.

Speaker #6: For abstracts, we're cepted. Including an overview of 36-month data from the ongoing XTOL open label extension study of as at your counter, and patients with FOS, which demonstrated sustained monthly reduction in seizure frequency, impressive seizure freedom rates, and a consistent AE profile suggesting long-term efficacy and tolerability of as at your unter.

Speaker #6: We also intend to highlight data from our XTOL study showing the efficacy of as at your counter in certain focal onset seizure subtypes, as well as present a targeted literature review outlining the comorbidity burden in focal onset seizures.

Speaker #6: In addition, our discovery team will present findings from our early-stage NAV 1.1 program with data from preclinical models of Dravet syndrome. Then, of course, we're also looking forward to the American Epilepsy Society later in the year having already submitted new four-year long-term data from our XTOL open label extension study with plans have a strong presence and opportunities for education and interactions with the various event plans.

Speaker #6: So, more to come as we get closer to engaging with the epilepsy community in Atlanta later this year in December. Turning to Xenon's efforts to expand its counter use into neuropsychiatry, I want to first highlight that XNOVO-3, the second of three planned Phase 3 clinical trials evaluating its counter in patients with major depressive disorder, has now been initiated alongside XNOVO-2.

Speaker #6: As we engage with physicians who treat patients and depression and are involved in the studies, they're eager to explore the differentiated profile of as at your counter versus existing agents.

Speaker #6: They're specifically interested in As at your counter's novel KV7 mechanism of action and its potential benefit on anhedonia, rapid onset of effect, along with a potentially differentiated tolerability profile.

Speaker #6: Echoing Ian's sentiments, I'm also pleased to announce that XSEED, the first of two planned phase three clinical studies evaluating as at your counter in patients with bipolar depression I and bipolar depression II, has been initiated.

Speaker #6: Bipolar disorder is a psychiatric condition characterized by mania, or hypomania, and depressive episodes and can severely impact a person's quality of life. As of 2019, approximately 40 million people worldwide were affected by bipolar disorder and nearly 6 million adults in the US.

Speaker #6: On average, patients diagnosed with bipolar disorder spend three times as many days with depressive symptoms than with mania, or hypomania. And the severity of depressive symptoms has been associated with functional impairment, reduced quality of life, and a higher prevalence of attempted suicide.

Speaker #6: Effective treatments for depression and bipolar disorder are limited in many patients who are non-adherent due to intolerability and side effects. In short, there remains a significant unmet medical need for safe and effective therapies to treat patients with bipolar depression.

Speaker #6: Now, our expanding into BPD is based on a strong scientific rationale based on preclinical data showing an antidepressant effect of as at your counter, genetic links between BPD and KV7, evidence of KV7 downregulation in BPD, as well as clinical studies that explore the use of KV7 potentiators in depression.

Speaker #6: Considering the treatment landscape for BPD, as at your counter's novel selective KV7 mechanism of action potential benefit on anhedonia, rapid onset of effect, and differentiated safety profile are particularly attractive in BPD.

Speaker #6: Further, we believe that as at your unter's demonstrated safety profile could represent an improvement over commonly used drugs to treat bipolar depression. Such atypical antipsychotics, lithium, valproic acid, and lamotrigine based on results from our phase two Xnova MDD study, where no study subjects experienced notable adverse effects on sexual function or weight gain.

Speaker #6: Our phase three BPD program includes two multi-center, randomized, double-blind, placebo-controlled clinical trials to evaluate the clinical efficacy, safety, and tolerability of 20 milligrams of as at your counter administered orally with food over the six-week double-blind period as monotherapy treatment in approximately 400 patients per study with bipolar I or II depression.

Speaker #6: With an opportunity to increase the sample size to 470 based on an interim analysis. The primary efficacy endpoint is the change from baseline in the moderate score at week six in patients who received as at your counter compared to placebo.

Speaker #6: Upon completion of the double-blind period, eligible patients may enter an open label extension study for up to 12 months. We feel it's important for us to address the use of moderates in this study compared with the use of HAMD 17 in the phase three MDD program.

Speaker #6: Scientific literature suggests that symptom presentation differs in unipolar versus bipolar depression. While HAMD 17 places emphasis on melancholic and somatic symptoms, which are more frequent in unipolar depression, it focuses less on atypical features of depression thereby limiting its utility in bipolar depression.

Speaker #6: In a study comparing BPD and MDD patient groups, bipolar patients scored lower on the HAMD 17 despite both groups scoring similarly on the Beck Depression Inventory and also the Global Assessment of Functioning.

Speaker #6: Thereby concluding that the severity of bipolar depression may be understated or underestimated by the HAMD-17 due to the different presentations of depressive symptoms.

Speaker #6: Further, since 2010, all clinical studies that led to approved therapies in BPD have used moderates as the primary endpoint. With this backdrop, we believe that the design of our XSEED registrational study supports our ultimate goal of seeking the approval for as at your counter in bipolar one and two depression.

Speaker #6: We're incredibly excited by the potential of as at your unter and its KV7 mechanism and neuropsychiatric indications, such as MDD and BPD. And I look forward to providing updates as we leverage as at your unter's pipeline in a mechanism potential across multiple streams of late-stage clinical development.

Speaker #6: Ian, I'd like to turn the call back to you now so you can provide an update on some of the great work happening in the earlier stages of our development pipeline.

Speaker #4: Great, thanks, Chris. There is significant momentum across our early-stage pipeline, with multiple regulatory filings expected this year to support the initiation of first-in-human trials across a number of validated IN channel targets.

Speaker #4: This broadening out of our early-stage pipeline is a direct result of the successful leveraging of our extensive knowledge and development expertise in potassium and sodium channel therapeutics.

Speaker #4: As our diverse pipeline of early-stage drug candidates continues to mature, I'm incredibly proud of the considerable progress we are making across multiple programs targeting the IN channels that include KV7, NAV1.7, and NAV1.1.

Speaker #4: Today, I'll give you an update on each of these promising programs. Beginning first with our pain programs, I'm excited to confirm that we have now initiated two Phase 1 studies within our KV7 and NAV 1.7 programs.

Speaker #4: Despite a wide range of therapies, many patients still suffer from inadequate pain control, poor tolerability, or dependence on opioids. The need for new non-opioid treatment options remains significant.

Speaker #4: We believe KV7 and NAV 1.7 are highly validated targets in pain as both mechanisms are central to pain signaling through their role in regulating neuronal excitability.

Speaker #4: Recognizing the potential broad applicability of the KV7 mechanism as a therapeutic counter, we've identified multiple chemically diverse KV7 development candidates and believe this mechanism may have utility in a broad range of therapeutic indications, including seizures, pain, and neuropsychiatric disorders such as major depressive disorder (MDD) and bipolar disorder (BPD).

Speaker #4: Last quarter, we indicated that a clinical trial application or CTA was accepted for Xenon 1120. This is a KV7 channel opener that we intend to study as a potential treatment for pain and a phase one study in healthy adult participants is underway.

Speaker #4: There is preclinical and clinical evidence supporting the development of novel selective KV7 openers optimized for pain, and we expect to identify a number of other KV7 molecules and chemistries that will follow Xenon 1120.

Speaker #4: We also continue to make substantial progress within our NAV 1.7 sodium channel program. Where we believe we may have addressed the limitations of earlier investigational drugs targeting NAV 1.7.

Speaker #4: A key part of Xenon's heritage involves our pioneering work that contributed to the strong human genetic validation of NAV 1.7 as a pain target.

Speaker #4: And we believe NAV 1.7 could represent a new class of medicines which address the unmet medical need effective alternatives to opioids. We have advanced multiple selective NAV 1.7 development candidates to date, and we're pleased to report that a phase one study has recently been initiated for Xenon 1701; this is our lead NAV 1.7 development candidate for pain.

Speaker #4: In early October, we plan to host an R&D webinar to showcase our early-stage pain programs that will include deeper dives into mechanisms, the underlying human genetics, preclinical results, and other supporting data.

Speaker #4: As well as an overview of disease prevalence and unmet medical needs within certain patient populations. We plan to share additional details as we get closer to the date.

Speaker #4: And we look forward to hosting a series of these virtual sessions in the future. Work within our NAV 1.1 program also continues to progress. Our preclinical work to date suggests that targeting NAV 1.1 could potentially address the underlying cause and symptoms of Dravet syndrome.

Speaker #4: Data shows that dosing with an orally available small molecule CNS penetrant and highly selective NAV 1.1 potentiator suppress induced seizures and improve motor performance, supporting the potential for improvements in Dravet patient motor function.

Speaker #4: Further, in these animal models, chronic dosing suppressed spontaneous seizures, projected against sudden unexpected death and epilepsy or SUDEP, and increased long-term potentiation of potential cellular correlate of learning and memory.

Speaker #4: These preclinical data are incredibly exciting, and we anticipate that a lead NAV 1.1 candidate will enter IND enabling studies later this year. Finally, also coming out of the Xenon labs is a promising selective dual inhibitor of NAV 1.2 and NAV 1.6, and this is now in a phase one study as part of our collaboration with Neurocurrent Biosciences.

Speaker #4: Neurocurrent has guided that this first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the investigational compound MBI 921355 in healthy adult participants to support its development for the potential treatment of certain types of epilepsy.

Speaker #4: I'll now turn briefly to our financial results. Cash and cash equivalents and marketable securities totaled $624.8 million as of June 30, 2025, and this compares to $704.4 million as of December 31, 2024.

Speaker #4: Based on our current operating plans, and this includes the completion of the as at your counter phase three epilepsy studies, as well as supporting late-stage clinical development of as at your counter in MDD and BPD, we anticipate having sufficient cash to fund operations into 2027.

Speaker #4: Given our proven track record of strong fiscal management, Xenon is in the fortunate position of having a ong balance sheet to support multiple registrational programs for as at your counter, and continued maturation of our early-stage pipeline.

Speaker #4: I would refer you to our news release and our 10Q report filed today for further details around our financial results. Before I offer a few concluding remarks, I did want to take moment to welcome Darren Klein, who joins our senior executive team as Xenon's chief commercial officer.

Speaker #4: And we'll lead our commercial strategy and operations, with an initial focus on as at your counter and our first potential launch in epilepsy. Darren is an incredibly experienced commercial leader with an enterprise-level mindset.

Speaker #4: Having led commercial organizations at multiple highly successful companies, that include GW Pharma and Cegen. He brings significant US and global launch experience and was instrumental in the commercialization of Epidiolex, which is considered one of the most successful launches in the epilepsy space.

Speaker #4: Darren, it's great to welcome you at this pivotal time, and I ow we can benefit from your extensive experience in epilepsy. And your strong record, strong track record of meeting commercial targets of successful product launches that have brought meaningful medicines to patients.

Speaker #4: Your addition to our leadership team also underscores the great talent that we've been hiring more broadly across the company. So, Darren, over to you for a few remarks.

Speaker #7: Thank you, Ian, for the warm introduction. I'm thrilled to join Xenon as Chief Commercial Officer at such a transformative moment. My experience in epilepsy has fueled my passion for addressing the unmet need of patients living with seizures.

Speaker #7: The data from the XTOL trial and the open label extension for as at your counter are truly compelling. Showcasing its potential to be paradigm shifting with its novel mechanism of action.

Speaker #7: I'm eager to connect with the epilepsy community at the International Epilepsy Congress in Portugal later this month, and to build momentum towards AES in December.

Speaker #7: At AES, we'll have the opportunity to share long-term data from our ongoing open-label extension (OLE) study, which continues to demonstrate impressive outcomes. Notably, the latest OLE data shows that approximately one-third of patients on our treatment for at least 36 months have achieved seizure freedom for a year or more.

Speaker #7: This is a meaningful metric, as many epileptologists tell us that seizure freedom translates directly into improved quality of life for people living with epilepsy.

Speaker #7: Joining Xenon at this juncture with the XTOL-2 database on the horizon and the potential approval of as at your counter in epilepsy is incredibly exciting.

Speaker #7: Looking ahead, the prospects for additional future indications in MDD and BPD further underscore the transformative potential for the company. I'm excited to engage with the investor community as we continue to make progress toward our goal of becoming a fully integrated commercial-stage neuroscience company.

Speaker #7: Ian, back to ou.

Speaker #4: Great. Thanks so much, Darren. The entire Xenon team is galvanized and driven by the strong potential of us at your counter and our broad pipeline of innovative neuroscience programs.

Speaker #4: We are entering a transformational period for Xenon as we evolve from a clinical to commercial stage company. We believe that positive top-line results from our phase three epilepsy program will enable an NDA submission to the FDA.

Speaker #4: With the goal of advancing our counter towards commercialization, a number of our other late-stage neuropsychiatric programs are now underway and recruiting patients.

Speaker #4: And our deep pipeline also contains multiple promising early-stage therapeutic candidates across a number of IN channel targets supporting our goal to be a premier neuroscience-focused company.

Speaker #4: On behalf of everyone on the Xenon team, we are incredibly excited by the advancements in both our late and early-stage programs, expansion of our pipeline, as well as how the team is preparing towards commercialization.

Speaker #4: And remain focused on taking important steps forward to bring us closer to delivering as at your counter to people living with epilepsy. So with that, that concludes the prepared remarks and operator, we can now open the call up for questions.

Speaker #8: Thank you. As a reminder to ask a question, you will need to press star then the number one on your telephone keypad. And if you would ike to withdraw your question, press star one again.

Speaker #8: Your first question comes from the line of Paul Mattis with Stifel. Your line is open.

Speaker #9: Hi, this is Emily on for Paul. Just a few quick questions from us. First, can you remind us again how quickly you think you'll be able to file on the back of that top-line FOS data?

Speaker #9: And then secondly, on the 1. NAV 1.7 program in pain, could you k to us a little bit more about your confidence in why you won't see safety issues like other drugs that have tried this same mechanism and target?

Speaker #9: Thank you.

Speaker #4: Great. Thanks, Emily. I can comment on both of those. So the first question on timing for filing after the XTOL-2 data. So although we haven't given guidance on this, I know we've spoken with a number of investors historically and we will.

Speaker #4: We will provide more specific guidance as we get closer to top-line and between top-line and NDA. But we think it's approximately six months from top-line data to filing the NDA.

Speaker #4: And then your second question on NAV 1.7. So I think you're probably referring that we have seen in the literature some cardiovascular signals with some of the earlier molecules that were in clinical development.

Speaker #4: So we believe that both the profile of the drug in terms of kind, both central and peripheral exposure, as well as the time to Tmax influences that.

Speaker #4: And we believe we have a good handle on it. We haven't seen any cardiovascular signals in any of the preclinical safety data, so we will obviously be monitoring it—something that we can monitor in human clinical development as well.

Speaker #4: But we're excited. I think the big progress is really getting that molecule into the clinic and showing a real leadership position in the NAV 1.7 space.

Speaker #8: Great. Thanks so much, and congratulations on the quarter.

Speaker #4: Thank you.

Speaker #8: Next question comes from the line of Tessa Romero with JP Morgan. Your line is open.

Speaker #10: Hi, Ian and team. Congrats on the progress here from us. So, for XTOL-2, when would you expect all the patients to be randomized?

Speaker #10: What was your patient recruitment split, U.S. versus ex-U.S.? And can you comment on how many sites you ultimately enrolled at for XTOL-2 and how many of them you used in XTOL?

Speaker #4: Great. Thanks, Tess. Chris, maybe the both of us can kind of tag team these. I can give a little bit of perspective, and maybe you can add some more details as you’re super close to the program.

Speaker #4: You know, we've recently finished, so maybe just take a step back in terms of timelines for XTOL-2. We've recently completed patient recruitment, which is what we've communicated today. This is a huge milestone for the company.

Speaker #4: And now we have a very definitive timeline as those patients move through towards top-line data. So the last patients will go through a baseline period, as ou know that baseline is eight weeks.

Speaker #4: And so then we would see the last patients randomized. So you know we can provide updates there. In the future, but there is that baseline period.

Speaker #4: And then there's the three-month double-blind period. After the randomization visit, there will be a safety follow-up, and obviously, database lock and data analysis. So that gives you a little bit of the timeline on data, so it'll be in the near future that we would have those last patients being randomized.

Speaker #4: You know, a bunch of your other questions, I think we should wait and see a little bit on this because we haven't randomized the final patients. We don't have specific breakdowns yet because these data are changing all the time.

Speaker #4: In terms of ex-U.S. versus U.S., how many sites of enrolled patients, and the comparison with the XTOL sites. But I don't know, Chris, if you want to provide any maybe directional guidance on what we saw in XTOL and maybe what you may expect to see in XTOL-2.

Speaker #6: Yeah. So I mean, I would just say on a high level, the spirit of XTOL-2 has been to try to stay as consistent with XTOL as possible since that study was wildly positive.

Speaker #6: And as far as the breakdown geographically, U.S. versus ex-U.S., I think it's going to end up being quite similar to Ian's point. We won't know the exact numbers for another eight weeks or so.

Speaker #6: And then on the total sites, there were fewer of the little fewer than 100 needed for XTOL and we're trying to we've you know we're randomizing more subjects in XTOL-2 versus XTOL.

Speaker #6: And so we have tapped into a larger number of sites. But we can share all that in detail when the time is right.

Speaker #8: Ian, Chris, have you seen any compassionate youth interest?

Speaker #4: You want me to take that?

Speaker #5: Yeah, we have. And yeah, Chris, go ahead if you want to address that.

Speaker #6: Constantly would be my one word. Response. Yeah. There's interest in this mechanism, you know, not just within necessarily the central nervous system, within neurology and psychiatry, but beyond.

Speaker #6: And so we have you know on a basis, we have incoming questions about using as at your counter in a number of situations. As you can see, you know on our website, we don't have a compassionate use program going right .

Speaker #6: We've had a lot of active discussions about you know when that approach could change. But more on that later as well.

Speaker #8: Thank you.

Speaker #4: Thanks, Tess.

Speaker #8: Next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is open.

Speaker #11: Hi. Good afternoon. Thanks for taking my question, and congrats on all the progress. So, you know I realize for XTOL-2, you still need to finalize randomization, but I'm curious if we should be sort of thinking this potentially as the study size in the end being larger than the 360 originally planned, sort of depending on how things go.

Speaker #11: Would the final screens and randomization, and then I assess along those lines? Some of our analyses had shown that phase two to phase three translatability in focal tends to be pretty good, with limited diminishment of the delta in seizure reduction.

Speaker #11: So I guess I'm curious if you could maybe speak to your latest assumptions for what the delta could be and what the dropout rate could be for the study as we think about powering.

Speaker #11: Thanks.

Speaker #4: Thanks, Brian. Chris, I'm happy to start and give my perspective and then you can add in, especially as you kind of think about the XTOL-2 readout.

Speaker #4: So Brian, in terms of your end number, so as you've spoke to, the study was designed for 360 subjects. It's three arms. 120 subjects per arm.

Speaker #4: That's approximate. So, we try to get as close to that as possible, but as you know, we had to stop patient screening at these individual sites before the final randomization numbers.

Speaker #4: And that screen and baseline failure rate can move around a ittle bit. And so I don't have a final number yet because we don't have it internally, but we'll y to get as close to that 360 as possible.

Speaker #4: And I think that's important. I don't think we have to kind of over-enroll, and maybe this is a bit of commentary to our second question.

Speaker #4: You know, as you've mentioned, and we agree with, I think reproducibility and translatability between different epilepsy studies and phase two to phase three are generally very good and very high.

Speaker #4: Definitely, in the neuro field, and we have lots of power at that sample size, right? We've talked about at the high dose of 25 milligrams, based on our phase two data as inputs into the model.

Speaker #4: We have more than 99% power. And at the 15 milligram dose, we have more than 90% power. So very, very comfortable in terms of the statistical analysis, how we've designed the study, the sample size, and the powering.

Speaker #4: You know, my perspective on what we need to see in terms of XTOL-2 is this study needs to be adequate for us to file.

Speaker #4: And we've had a very successful readout in XTOL. And so the second study, XTOL-2, you know, we need it to be statistically significant and we need for that to support an NDA filing because now that XTOL already complete, we have those data in hand.

Speaker #4: And as we've talked about previously, I think they're remarkably robust. You know, on a placebo-adjusted basis, it's the efficacy we've ever seen in a focal onset seizure study.

Speaker #4: In the most refractory or severe population ever tested, at least our review of the literature. So now that that's already completed, I really think that the bar is we need statistical significance.

Speaker #4: We expect to see, obviously, some consistency. We're seeing that in the baseline demographics and the data going into the study. And that would support a filing.

Speaker #4: But Chris can probably provide his perspective as well.

Speaker #6: Yeah. Thanks, Ian. And I think you largely covered . When we you know, there's a limitation to what we can see in a blinded phase three study that's ongoing.

Speaker #6: But when we look at the patients that are coming in to the sites that are being screened and then who is making it through the screen failure and the baseline process, there's some metrics we can look at during the double blind and then looking at rollover into the open label.

Speaker #6: Everything is moving as we would have expected. You know, given the limitation that it's a blinded study. And when we look at metrics that have historically driven placebo responses, like geography, we've been pretty careful on that front as well.

Speaker #6: So you know, it's hard to imagine that two large studies will have the exact same delta. But when we take look at the major drivers of that delta from our own data and from other studies, we're feeling like you know, as comfortable as we can considering that it's still a blinded study.

Speaker #4: Thank you very much. Thanks, Brian.

Speaker #8: Next question comes from the line of Brian Courtney with Beard. Your line is open.

Speaker #4: Brian, can you hear us?

Speaker #12: Yep. Sorry about that. Thank you for taking the estion. On 1701, can you talk a little bit about the molecule's profile? Do the preclinical models indicate PK and bioavailability conducive to one staley or more frequent dosing?

Speaker #12: Can it be developed in an IV formulation? And how are you thinking about the first clinical pain model to serve as proof of concept here a postoperative pain, a severe pain model, or more along the lines of a moderate pain indication?

Speaker #12: Thanks.

Speaker #4: Thanks, Brian. Lots of questions in there. If I don't them all, I've please jump back in and just remind me of any other ones that I may have missed.

Speaker #4: So on your first question of PK, I mean, we'll be able to answer that question very shortly as we get through the first number of cohorts in humans.

Speaker #4: Still, we believe one of the challenging parts of drug development is that extrapolation and that prediction of human PK from animal PK. So, you know, we will, you know, obviously, we're designing drugs that we believe are going to have appropriate half-life, but we really need some early clinical data in humans to be able to answer that question specifically.

Speaker #4: So we'll get back to you on that as we start to see some data. You know, I think there is in you know, in epilepsy and in pain, I think there's always an opportunity for to have an IV formulation as well as an oral formulation.

Speaker #4: These initially, either we look at as at your counter or 1701, these are being developed as oral drugs. Usually, the IV development comes a little bit later.

Speaker #4: But it's something that we're keeping in mind and keeping an eye on. We're doing that work for as you're under. And we'll do work for 1701 and the other NAV 17 candidates as well, because I think I know where you're going with that question.

Speaker #4: I think there's a good opportunity if you can have an IV drug, you know, an formulation of the same molecule and then also the oral pills that the patient can go home with.

Speaker #4: So you know, more to come there, but something we definitely think about internally. And some of these details will address in our webinar that we're going to in early October, where we're ing to highlight both KV7 and NAV 1.7 for pain.

Speaker #4: And then in terms of the proof of concept study, so this would be so we haven't fully designed out the phase two proof of concept study for either 1120.

Speaker #4: The KV drug or for 1701, but we are looking at the postoperative setting and looking at things like bunionectomy and a domino plasty. And are trying are really now now that both of those are in a phase one study, you know, bringing the team together to best design those proof of concept studies and probably thinking a lot of the same things that you're thinking about in terms number of doses and controls and a number of other things that we would contemplate into those studies.

Speaker #4: Did I catch all of them? You got it, Ian. Thanks so much. Okay, cool. Thanks, Brian.

Speaker #8: Again, everyone, if you would like to ask a estion, press star then the number one on your telephone keypad. Next question comes from the line of Jason Gerberry with Bank of America.

Speaker #8: Your line is open.

Speaker #4: Hey, guys. Thanks for taking my questions. Just another XTOL-2 question now that enrollment's complete. And in terms like the blinded demographics, I'm just curious to the extent you know maybe severity if you've had a chance to assess that to look similar to XTOL-1.

Speaker #4: I know a competitor in the space ended up enrolling less severe patients, and we're just kind of wondering if that's perhaps company-specific or maybe an industry trend.

Speaker #4: And then with your BPD study, do ou anticipate a high degree of site overlap with MDD? I'm just wondering if there's an portunity for accelerated enrollment of the BPD study.

Speaker #4: And then just lastly, I think there was comments that with these healthy volunteer pain studies that there'd be some sort of induced challenge to assess efficacy parameters.

Speaker #4: I know there's some debate around the utility of those, but I'm just kind of curious if that's something that you'll be assessing in those Phase 1 pain studies.

Speaker #4: Thanks. Thanks, Jason. Chris, I'm happy to take maybe the first one and the third one if you want to comment anything else you want to add on XTOL-2.

Speaker #4: And then if you want to address the bipolar depression MDD question. So Jason, when you've asked just about the baseline blinded demographic data, as it relates to patient severity for XTOL-2, as we mentioned on our last call, and we confirmed again today, those the patient characteristics are looking very much like XTOL.

Speaker #4: And again, we don't have final data there because patients are still getting randomized, so we don't have the final sample size to be able to get a final answer there.

Speaker #4: But it's looking more like the XTOL in terms of those main demographics that we look at at baseline. My perspective, and I think Chris should provide his as well, is that in these studies, the patients are becoming more severe over time, not less severe over time.

Speaker #4: I know you referred to a recent data set from a competitor that may have had a less severe population. I mean, I think I know the one you're referring to, and I think that was an open-label study with an incredibly small sample size.

Speaker #4: I wouldn't draw too many conclusions from that. But I think our experience is that the patient demographics and the severity over the last kind of 10 or 20 years, when we go back to some of the earlier generation ASMs, those were in a much less severe population.

Speaker #4: Now, we're the company that has run the two most significant studies in this space over the last five years. And so I think we have a really good perspective on that.

Speaker #4: But I think Chris can add to my comments. And then your third question, just on any kind of pharmacodynamic endpoint in pain studies, yeah, those are highly variable.

Speaker #4: There's a number of things that you can do. They're highly variable. And then they you ow the question is always whether they're powered appropriately or not.

Speaker #4: I think you know we're . So our perspective is really what we're trying to arn about in phase one you know in addition to PK and safety is make sure that we have the appropriate amount of exposure that based on our preclinical modeling we would believe that we should see an analgesic effect.

Speaker #4: And then let's get into a patient population and run a proper proof of concept study and be able to measure it that way. So that's really been the guiding principle at Xenon.

Speaker #4: And we believe we can have two of those proof of concept studies for 1120 and 1701 next year. Chris, do you want to add to the first one and then the question on bipolar and MDD?

Speaker #6: Thanks, Ian. Yeah, I don't have anything to add to either one of those two questions that you answered. I think you covered it in its totality.

Speaker #6: On the BPD and MDD front and site overlap, we've you know built up a really nice robust relationship with our epilepsy sites and we've beyond that within the epilepsy community.

Speaker #6: We are now starting to do that with the psychiatric community as well to some extent, particularly the sites. And so I do expect that there'll some degree of overlap with sites between MDD and BPD.

Speaker #6: And there will be some leveraging of resources there that is sort of analogous to how we've done focal onset seizure and primary generalized tonic-clonic seizures in the epilepsy program.

Uh, thanks Andrew. Um, I'll provide a high level comment and then Chris, if you can get into the details on on a little bit around the sizing and and the, you know, obviously this is being designed as a, as a registration program. Um, you know, Andrew, I think, although we believe we have really good support for going into bipolar depression. And we've talked about that mechanistic rationale, there's some genetic validation, um, that that we're really excited to get in into the bipolar study and get that up and running. We do not have current clinical data in bipolar depression. And that was really, the reason behind giving us some flexibility in the trial design and so an opportunity to, um, be able to increase the size of the study.

We sat in the prepared remarks um, from 400 subjects up up to 470, um, but Chris can walk you through a little bit more detail there.

Yeah, thanks. Um I mean we we don't know exactly when that intrum analysis will take place because it's it's based upon Recruitment and we obviously have projections of recruitment but it's the early days of the study.

I mean, to Ian's point, the interim analysis will be done in a manner so that if the study is found to have insufficient power at 400 patients, that could be overcome by increasing to an intermediate number up to 470. Then we’ll do it. Um, and I think I’m just going to leave it at that for now.

Thank you.

Thanks Andrew.

Next question comes from the line of Corey Khasanov. Your line is open.

Guys, thanks for taking the questions, I guess, 2 from me. Um, first on the competitive front curious, how you see the potential read through of, uh, from biohaven pending MDD readout? That's expected at some point in the second half over to. Is that a cal nurse xn? Nova MDD program, I guess. Maybe I'm that front it would help if you can just remind us of the key differences between the 2 assets and then second question is for Darren. Um and Darren good to be covering you again, recognizing its early days.

And I know there's a lot of excitement about a new mechanism of action with this kind of overall profile in the medical community. But I'm curious how you're thinking about some of the key headwinds and just general nuances of the epilepsy Market that you'll have to deal with upon approval and launch. Thank you.

We are comfortable with the mechanism in major depressive disorder. We've seen, you know, a number of studies, uh, 2 with our molecule. Um, both, um, The xaenova Phase 2 study that we ran that proof of concept, as well as the investigator LED study, that that was announced earlier this year. And then there was some earlier data with his agabin, as well. So I think we feel comfortable in terms of the mechanism, um, as having activity and support in psychiatric disorders. And, and at the top of that list in terms of validation, uh, is definitely MDD based on the clinical data. So, you know, I think it'll be interesting, we haven't seen any efficacy data yet with the biohaven molecule from the placebo controlled study. So I I still think there's maybe some molecule specific questions as it relates um to to that molecule. Um but I think in terms of um the therapeutic indication we think obviously that makes a lot of sense. And so you know we'll be we'll be looking um to

See what those data show and and and can provide our perspective at that time. I'm not sure. There's too much we can say in advance of that. But I know Darren's really excited to, uh, to be on the call and to start uh, preparing. I think Darren you're 6 weeks in. So yeah. Starting to to think about prepping is that your calendar for the epilepsy Market? Yeah, thanks and hey, hey Corey good to hear from you again. I saw your name and I was very pleased. Uh yeah, I'm super excited to be at Xenon. Um, I think when you look at the this epilepsy,

The space specifically focuses on focal seizures, you know, with the Zetu calendar being, you know, the first.

Or the latest branded launch in, you know, at the time it’s going to be 7, 8 years, a tremendous amount of opportunity. And I think, you know, you hit on a couple of those. I think the...

The, the novel mechanism of action, the robust efficacy, we've seen the rapid onset, uh, of effect. Um, a lot of and what we hear, also, the east of attributes, uh, 1 daily dosing, and no titration, I think it's a, it's a perfect opportunity for us to really make a difference. I think, when you think about headwinds, um, it will be, I think we look at these epileptologists and gender General neurologists. Um, there's somewhat set in their ways and I think we'll have to overcome some inertia that has been built in there with some, um, therapies that still don't need them. Meet the needs of a lot of patience and a lot of Physicians. So, um, very excited. Uh, again early days a lot of work to do but I think we have an asset here and is that 2 calendar. Can really make a difference uh in this epilepsy community.

Great, very helpful. Thank you.

Next question comes from the line of Mark Goodman with Ling Partners. Your line is open.

Hi, good afternoon. Thank you for taking our question. This is basmo on for Mark. Uh, could you please provide some color on the difference between the type 1 and type 2 by further depression? And um whether would you expect that as a, as a 2 Corner would be more effective in 1 patient population versus the other. Um, and also can you

Can you please? Let us know if you assessing Mania as a secondary point of the trials or not. Uh, that's it for us. Thank you.

Great. Thanks for the questions Chris over to you for these 2. Yeah sure. So just to be clear the the bipolar depression studies will include a mixture of type 1 and type 2 BPD. The type 1 or the patients that have Frank manic episodes and the type 2 patients or those who have hypomania.

Um and what we're doing is we're we're stratifying so that in in each treatment group there won't end up being an imbalance between BPD 1 and 2 depending on whether they receive active or Placebo. And and that's being driven by the fact that we don't really know what the effect will be in 1 versus the other. We're going into it with the belief that it should work just as well in BPD 1 and 2, but we don't know that until we until we run the the experiment.

Which is a whole Litany of assumptions, then at least it provides some.

Um, you know, uh, sort of comfort that the this mechanism doesn't exacerbate Mania, we don't think it will, but we'll kind of keep a close eye on it.

Great. Thank you. That's very helpful.

Next question comes from the line of Joseph stone with TD Cowen. Your line is open.

Hi there, good afternoon. Congrats on the progress and thank you for taking my question. Um, maybe on the kb7 for, for paying obviously, um, libertine showed some some anti-pain activity, but it ended up seeing some some liver toxic signals, so I guess. Um, how confident are you that you can de-risk, uh, potential liver, toxicity pre-clinical through avoiding. Um, you know, any sort of toxic metabolites generation and kind of what have you seen there and then have any of the quality of life measures that you've collected for, as I to call her um related to to pain at all. And last just a a kind of upkeep question. When we see the Topline release what what level of detail will we will we see what we also see seizure Freedom rates, in addition to um production and in the future. Thank you.

Uh, thanks Joe. Uh, bunch of questions there. If I miss 1 just uh just circle back. Um,

So I'll uh Chris, I'm happy to take the first 1 and the last 1 and maybe you can talk about um or at least us looking at um, at migraine and the xold program is, is 1 of the exploratory endpoints. Um, so Joe as it relates to 1120 and and KV as as as you mentioned in pain, um there was this molecule that was developed previously. That actually had some really interesting activity in in a number of different pain indications which is the molecule flu protein. It was commercially available and then it was removed from the market. As you said for liver tox issues obviously, you know, nothing in that. Um, we believe is to suggest that there's anything that's on target there. So that's always a risk in small molecule drug development and and so something that we monitor closely and and we think about in terms of, as all of the criteria in terms of a molecule. So we we have, you know, early days but but no concerns right now, um, in terms of xn, 1120, but obviously we need

A lot more exposure to to make any definitive statements there but we feel good where we are right now.

Um, and then in terms of the Excel 2 details, you know, at least historically. And I'm, I'm thinking back to both the Excel results. We had a few years ago, as well as our MDD results in xnova. I think we have a good amount of information in our Topline press releases and a nice balance. Um, kind of across the board of patient demographics. Efficacy endpoint safety endpoints to really give you

And and and investors a good handle on the overall profile of the molecule. So I think you can use those as a bit of a template. We haven't come up with the final, uh, tfls and, and everything that we'll ask the stats group to to do a Top Line. Obviously, we can't get to everything, um, but I think you'll see a good amount of information in there. And then, always more information will come out at subsequent medical congresses and meetings as well. Um, Chris maybe you can contact or talk about the quality of life measures, um, question that Joe had and and maybe the phase 3 epilepsy programs early. So that

Yeah, so quality of life on a, on a high level, we have shared our quality of life data which shows, compelling improvements in quality of life, particularly in the Excel open label. Um that that poster is actually on our website if you care to look at the at the details. Um, and then as far as pain goes, yeah, you're you're absolutely right. Flipper team. You know has been was used for years and and appears to have been useful for pain. Um, you know, the the I I would just, you know, a little bit of caution that the the mechanism of flu protein. It's not a totally clean kv7 compound. And so I think that there's somewhat of a read out there but I wouldn't Bank everything on that. I think, you know, it's really the, the preclinical experiments and and kind of a vast literature that I think is supports that. But we have, you know, as Ian said in his remarks like nearly 800 patient years of exposure and we have no

And epilepsy and so, um, so yeah, I mean, it's not the most important thing about that study. But we'll, we'll, we will get somewhat of a readout in terms of pain from the phase 3, epilepsy study. The caveat there is we're not enriching for, you know, migraine headache in the manner that we are for for, you know, seizures but um so it will be limited, but there will be some some sort of a readout there down the road.

Great. Thank you.

Thanks Joe.

And our last question comes from the land of Paul Choice with Goldman Sachs your line is open.

Hi. Uh, thanks for squeezing me in, um, maybe for either Ian or Chris to, to start. Um, now, that you've, uh, completed an enrollment in the phase 3, could you maybe give us your, your latest thoughts on just, uh, how you're thinking about that. Uh, potential difference in dose response for the 15 and 25 Meg doses versus, uh, the dose response we saw in the phase 2 and as part of your filing strategy, uh, is the plan to, you know, definitely go with both doses or just maybe the minimally efficacious dose, uh, and maybe that as a first question and then um, second um, on the the uh, the nav 1.7 program. Once you establish proof of concept. Would you contemplate exploring combinations with a 1.8? I think 1 of your competitors. In the space is examining that just just your thoughts on potentially looking at dual targeted therapies here. Thank you.

Uh, thanks Paul. Um,

Maybe I'll take the 1, 7 question first, and then Chris, I can provide some perspective. Uh, and but definitely, um, give your give your comments on the dose response and and kind of what we're thinking about not only from the phase 3 program but in terms of regulatory filing. Um, so yeah, I mean, Paul. I think we're we're excited. I think we're in a leadership position in 17 to get a molecule now into the clinic and get first to proof of concept. I mean, that's really what's driving us there. Your question is a little bit of a broader 1, which is ultimately what are maybe different combinations that we could think about with different mechanisms, whether it be, you know, nav 1.7 nav 1.8, as you mentioned but also our KV mechanism that we're incredibly excited about. You know I think long term um yes maybe different combinations of these different non-opioid mechanisms may be the best to combine together. We're not going to see that in 1st 3 would be our perspective and so this would be combining different molecules that may

Have the best analgesic effect um, kind of long term but pretty early to start kind of thinking about that. But, but I think longer term you're thinking about, I think some really interesting questions from a development perspective.

Um, getting back to epilepsy, which I think is a nice way to finish, um, in terms of, you know, the recruitment being complete now. Um, so, 15 milligrams was not a dose in Phase 2. We saw a clear dose response between 10, 20, and 25 milligrams in the Xtool study. You know, we would expect, uh, all else being equal, that we'd see a dose response between 15 milligrams and 25. In the Phase 3 program, in our perspective is really in our discussions with the FDA so far, is to have more doses on label rather than less. Um, and that's really driven by we know that there's going to be a different exposure relationship depending on the individual patients and some of the background medications. Thus, providing as much flexibility as we can to the epilepsy community and the epileptologists and neurologists, we think is incredibly important here. Um, I know Chris will give you more detail in his perspective as a neurologist. But I think, um, having multiple doses available, um, is being consistent with our discussions with the FDA.

To date, and consistent with what we would think about in terms of filing the NDA.

Chris.

Yeah, just a couple quick things to add. Our PK/PD analysis of the Excel study suggests that we should have an intermediate response between what we saw in the 10 milligram and the 20 milligram doses in Excel. Um, we will find that out soon. I think Ian's point about having multiple doses approved is extremely important. And then, just I'll end with a parting comment, which is that you only need about...

About 40, maybe 50 patients per arm to be to have a 90% power. If you're just assessing, 25 milligrams, is that you in a focal onset, seizure study. Uh, so the study is really powered at 90% or maybe even a little bit more for the 15 Mumford.

Okay, great. Thank you. Thanks, Chris. Thank you, Paul.

Includes. Okay, and a session.

Exactly.

For closing remarks.

Thanks for everyone joining us today and I do want to pass my credit to the entire Xenon team. This was an incredibly productive quarter. Um, you know, for the first time we've completed enrollment and recruitment in our phase 3, epilepsy program and xtool 2. And we're excited that we're getting close to Topline data. But we also initiated 2 phase 3, clinical trials, within the quarter, both in, in the psychiatric program, with. Bipolar being up and running and our second MDD study and getting our nav 1.7 and real leadership positions there into the clinic as well. So incredibly productive quarter on the Xenon side, um, I know we didn't get to all the questions today. Um, happy to follow up with people 1-on-1 after the call, um, but thank you for all of your support. Uh, and operator. We can now end the call.

gentlemen, that's

cool. Thank