Q4 2023 Xenon Pharmaceuticals Inc Earnings Call

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Operator: Good afternoon. My name is Jeannie, and I will be your conference operator today. I would like to welcome you to the Xenon Pharmaceuticals, Inc. Earnings Conference call. All lines have been placed on mute to prevent any background noise.

Jamie: Good afternoon. My name is Jamie and I will be your conference operator today I would like to welcome you to the Q4 2023 Xenon Pharmaceuticals, Inc earnings Conference call.

Jamie: All lines have been placed on mute to prevent any background noise.

Operator: After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star 1 again. Thank you. I would now like to turn the conference over to Sherry Aulin, Chief Financial Officer. You may begin your presentation. Good afternoon.

Jamie: After the speaker's remark will be a question and answer session. If you would like to ask a question during that time simply press star followed by the number one on your telephone keypad.

Jamie: If you would like to withdraw your question Press Star one again thank.

Jamie: Thank you I would now like to turn the conference over to Sherri Olin Chief Financial Officer, you May begin your conference.

Sherry Aulin: Good afternoon. Thank you for joining us on our call and webcast to discuss the announced fourth quarter and full year 2023 financial and operating results. Joining me today are Ian Mortimer <unk>, President and Chief Executive Officer, Dr. Chris Kenny <unk>, Chief Medical Officer, and Dr. Chris One figure in.

Sherry Aulin: Thank you for joining us on our call and webcast to discuss Xenon's fourth quarter and full year 2023 financial and operating results. Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer, Dr. Chris Kenney, Xenon's Chief Medical Officer, and Dr. Chris von Seggern, Xenon's Chief Commercial Officer. Ian will begin with a summary of our recent progress and areas of focus for 2024. Chris Kenney will provide an overview of our ongoing XTN 1101 clinical programs, including our plans for major depressive disorder or MDD. And Chris von Seggern will comment on key findings from our market research on the potential of XTN 1101 in the MDD treatment landscape. I will close with a summary of our financial results and anticipated milestone events before opening the call to your questions.

Sherri Olin: The non as Chief commercial officer.

Sherri Olin: Ian will begin with a summary of our recent progress and areas of focus for 2020 for Chris Kenny will provide an overview of our ongoing.

Sherri Olin: 101 clinical programs, including our plans and major depressive disorder or M. D D and crisp on Sanger and will comment on key findings from our market research on the potential of actually getting a lot of an L Y N D. M D D treatment landscape.

I will close with a summary of our financial results and anticipated milestone events before opening the call up to your questions. Please.

Sherry Aulin: 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 our and our collaborators' clinical trials, the potential efficacy, safety profile, future development plans, the addressable market, regulatory success, and commercial potential of our and our partners' product candidates, the effectiveness of our clinical trial designs, our ability to successfully develop and achieve milestones in our Xeon 1101 and anticipated enrollment in our clinical trials and the timing thereof, and our expectation that we will have sufficient cash to fund operations into 2027. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statement.

Sherri Olin: Please be advised that during this call we will make a number of statements that are forward looking including statements regarding the timing and potential results from our and our collaborators clinical trials the potential efficacy safety profile future development plans addressable market regulatory success and commercial potential.

Sherri Olin: Of our and our partner product candidates.

Sherri Olin: Because of our clinical trial designs, our ability to successfully develop and achieve milestones in our <unk> 11 O one and other in development programs, the timing and results of our interactions with regulators our ability to successfully develop and obtain regulatory approval a vaccine 11 O one and our other product candidates.

Sherri Olin: Anticipated enrollment in our clinical trials and the timing thereof, and our expectation that we will have sufficient cash to fund operations into 2027.

Sherri Olin: Forward looking statements are subject to numerous risks and uncertainties many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings.

Sherri Olin: Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward looking statement.

Ian C. Mortimer: Today's press release summarizing Xenon's fourth quarter and full year 2023 financial results and the accompanying annual report on Form 10-K will be made available under the investor section of our website at www.xenon-pharma.com and filed with the SEC and on CDAR. Now, I'd like to turn the call over to Ian. Thanks, Sherry, and good afternoon, everyone, and thanks for joining us on our call today. We are proud of the significant progress made across our pipeline in 2023, including the advancement of XEN11-01 in our broad Phase III epilepsy program, as well as strong execution in our Phase II Ex Nova clinical trial, which culminated in the release of top-line data in late November that demonstrated XEN11-01 to have clinically meaningful drug activity in patients with major depressive disorder, or MDD.

Sherri Olin: Today's press release summarizing xenon its fourth quarter and full year 2023 financial results and the accompanying annual report on Form 10-K will be made available under the investors section of our website at www Dot xenon dash pharma dot com and filed with the SEC and on SEDAR now.

Sherri Olin: Now I'd like to turn the call over to Ian.

Thanks, Jerry and good afternoon, everyone and thanks for joining us on our call today.

Ian C. Mortimer: We are proud of the significant progress made across our pipeline in 2023, including the advancement of <unk> hundred one and our broad phase III epilepsy program as well as strong execution in our phase II <unk> clinical trial, which culminated in the release of top line data in late November the demonstrated actually had 11 I wanted to ask.

Ian C. Mortimer: Cleaning clinically meaningful drug activity in patients with major depressive disorder or <unk>.

Ian C. Mortimer: In addition, we've made considerable progress in the maturity of our discovery portfolio, which I will expand upon in a moment. Our team has made excellent progress since the release of Ex Nova, which includes completing a capital raise in December to fully fund a broad phase three program in MDD and setting a date for an end-of-phase two meeting with the FDA in April. We have also taken meaningful steps towards designing our Phase III program and are committed to initiating the first of three planned Phase III clinical trials in the second half of this year. XEN11-01 is the most clinically validated and advanced KV7 therapeutic in development across multiple indications, and we believe the mechanism may have broad applicability. This is reflected in our comprehensive strategy to pursue multiple indications with XCN 1101, while also advancing additional novel KV7 drug candidates. Our extensive know-how, developed over almost two decades in ion channel drug discovery as well as our experience with potassium channels, positions us to maintain a leadership position in the KV7 space.

Ian C. Mortimer: In addition, we've made considerable progress in the maturity of our discovery portfolio, which I will expand upon in a moment.

Ian C. Mortimer: Our team has made excellent progress since the release of Ax, Nova which includes completing the capital raise in December to fully fund our broad phase III program at M. D D and setting the date for an end of phase two meeting with the FDA in April.

Ian C. Mortimer: We are also taking meaningful steps towards designing our phase III program and are committed to initiating the first of three planned phase III clinical trials in the second half of this year.

Ian C. Mortimer: I can't 11 to one that has the most clinically validated and advance <unk> therapeutics in development across multiple indications and we believe the mechanism may have broad applicability.

Ian C. Mortimer: This is reflected in our comprehensive strategy to pursue multiple indications with vaccine 11, a one while also advancing additional novel <unk> seven drug candidates are extensive knowhow developed over almost two decades and ion channel drug discovery.

Ian C. Mortimer: As long as our experience with potassium channels positions us to maintain our leadership position in Mckenzie <unk> space and.

Ian C. Mortimer: And we plan to continue exploring the pipeline in the potential of XEN11-01 and earlier stage drug candidates. We've made strong progress in our KV7 preclinical program in 2023, including the identification of several promising product candidates, and we expect more than one candidate will be in high-end enabling studies this year, and if successful, could enter first in human studies next year. Looking beyond our robust research and development efforts in the KV7 space, we are also advancing development candidates targeting sodium channels, including NAV1.1 and NAV1.7, which may have utility in treating seizure disorders and pain, respectively. We are uniquely positioned to develop molecules targeting NAV1.7, given the previous pioneering genetic research conducted by xenon scientists that suggests that this particular sodium channel is a key target for the development of novel analgesics.

Ian C. Mortimer: And we plan to continue exploring the pipeline and a mechanism potential vaccine on 11 to one and earlier stage drug candidates. We have made strong progress in our <unk> preclinical program in 2023, including the identification of several promising product candidates and we expect more than one Canada will be an IMD, enabling studies.

Ian C. Mortimer: This year and if successful could enter first in human studies next year.

Ian C. Mortimer: Looking beyond our robust research and development efforts and the <unk> seven space. We're also advancing development candidates targeting sodium channels, including NAV 1.1, and NAV, one seven which may have utility in treating seizure disorders and pain respectively.

Ian C. Mortimer: We are uniquely positioned in developing molecules targeting NAV one seven given the previous pioneering genetics research conducted by xenon scientist that suggests that this particular sodium channel is a key target for the development of novel Analgesics.

Ian C. Mortimer: We have made considerable progress in this program in 2023 and anticipate that multiple NAV1.7 candidates could also enter high-end enabling studies over the next few years. The benefit of this program is the opportunity to generate important, early, de-risking human proof of concept. So the considerable progress made in 2023 puts us in a strong position as we enter this year, where we have three key areas of focus.

Ian C. Mortimer: We have made considerable advancements in this program in 2023 and anticipate that multiple NAV. One seven candidates can also enter Indian enabling studies over the next few years. The benefit of this program has the opportunity to generate important early derisking human proof of concept data.

Ian C. Mortimer: So the considerable considerable progress made in 2023 puts us in a strong position as we enter this year, where we have three key areas of focus one the continued execution on our phase III epilepsy program with a specific focus on export too as this is on the critical path to an NDA filing and potential approval.

Ian C. Mortimer: One, the continued execution of our Phase III Epilepsy Program, with a specific focus on XTOL2, as this is on the critical path to an NDA filing and potential approval for XTN1101. Second, the expansion of XEN 1101 beyond epilepsy, with our now planned phase three program in MDD, while we continue to evaluate other clinical indications given XCN 1101's compelling profile. And third, the continued maturity of our discovery portfolio, with multiple molecules expected to move into human clinical development over the next few years. So, in summary, with a strong balance sheet to support our robust clinical and preclinical plans, we are looking forward to advancing and growing our broad pipeline with the goal of improving outcomes for patients in areas of high unmet medical need.

Ian C. Mortimer: Fracs Gen 11 on one SEC.

Ian C. Mortimer: Second the expansion of <unk> 11, and <unk> beyond epilepsy with are now planned phase III program in M. D. D. While we continue to evaluate other clinical indications given axion 11 O one's compelling profile.

Ian C. Mortimer: And third the continued maturity of our discovery portfolio with multiple molecules expected to move into human clinical development over the next few years.

Ian C. Mortimer: So in summary, with our strong balance sheet to support our robust clinical and preclinical plants. We are looking forward to advancing and growing our broad pipeline with the goal of improving outcomes for patients in areas of high unmet medical need.

Ian C. Mortimer: I'll now turn the call over to Chris Kenney, who will provide some more details on the progress within our XCN 1101 clinical program in both epilepsy and depression. Chris von Segern will then provide an important summary of recently completed market research providing feedback from physicians in the depression space to underscore the promise we believe XEN1101 has for broad therapeutic utility. So Chris, over to you.

Ian C. Mortimer: I'll now turn the call over to Chris Kenny who will provide some more details on the progress within our actually at 11 O. One clinical program in both epilepsy and depression.

Christopher John Kenney: Chris one sector and will then provide an important summary of recently completed market research providing feedback from physicians in the depression space to underscore the problem.

Speaker Change: <unk> <unk> hundred 11 has actually had a 11 one has for broad therapeutic utility.

Christopher John Kenney: Thanks, Ian. To echo Ian's comments, I'm proud of the many accomplishments achieved in 2023 by our development team and the advancements made across Xenon's preclinical and clinical product portfolio. We continue to receive overwhelmingly positive feedback on XEN11-01 from both clinical investigators, as well as the broader neurological community. At the annual meeting of the American Epilepsy Society in Orlando this past December, we had the opportunity to present 30-month data from the ongoing XTOL Open Label Extension Study, demonstrating impressive seizure freedom, including almost one in four patients who were on treatment for two years or more, achieving at least 12 months of consecutive seizure freedom. In addition, we've now generated more than 600 patient years of safety data, with some patients having been on Exxon 1101 for more than four years, supportive of a well-tolerated drug. Given the compelling data generated both in our Phase 2b XTOL study and ongoing open label extension, as well as from our recent XNOVA MDD study, we continue to hear that physicians are enthusiastic about the profile of XEN11-01 as we advance Our ongoing XEN 1101 Phase III Epilepsy Program includes our XTOL-2 and XTOL-3 clinical trials in patients with focal onset seizures, or FOS, and the XACT Clinical Trial in Patients with Primary Generalized Tonic-Clonic Seizures, or PGTC.

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Christopher John Kenney: Thanks, Ian to Echo <unk> comments I'm proud of the many accomplishments achieved in 2023 by our development team and the advancements made across as you know in its preclinical and clinical product portfolio.

Christopher John Kenney: We continue to receive overwhelmingly positive feedback on <unk> 11 O. One from both clinical investigators as well as the broader neurological community at the annual meeting of the American Epilepsy Society in Orlando. This past December we had the opportunity to present 30 months data from the ongoing X Tole open label extension.

Christopher John Kenney: Demonstrating impressive seizure freedom rates, including almost one in four patients who are on treatment for two years or more.

Christopher John Kenney: Moving at least 12 months of consecutive seizure freedom.

Christopher John Kenney: In addition, we've now generated more than 600 patient years of safety data with some patients having been on exon 11 O. One for more than four years supportive of a well tolerated drug profile.

Given the compelling data generated both in our phase two B X Tole study and ongoing open label extension as well as from our recent ex Nova MDT study. We continue to hear that physicians are enthusiastic about the profile of <unk> 11 O. One as we advance our late stage development plans.

Our ongoing exon 11 O one phase III epilepsy program includes our ex told two and X tole three clinical trials in patients with focal onset seizures or force and exact clinical trial in patients with primary generalized tonic clonic seizures or P. G Tcs.

Christopher John Kenney: In our news release today, we refined our guidance for the completion of X-Tol2 patient enrollment to late this year or early 2025 to reflect our current. As a reminder, we intend to submit an NDA upon the successful completion of XTOL-2, our first XCM-1101 Phase III clinical trial, along with the existing data package from our Phase IIb XTOL clinical trial and additional safety data from other clinical trials to meet regulatory requirements. Turning now to our work in major depressive disorder, and as Ian indicated in his comments, we believe the Ex Novo results were compelling and supportive of continued clinical development of XEN11-01 in MDD. To summarize the findings from Ex Novo, XEN11-01 demonstrated clinically meaningful dose-dependent activity in depression and anhedonia.

Christopher John Kenney: In our news release today, we refined our guidance for the completion of ex told to patient enrollment to late this year or early 2025 to reflect our current modeling.

Christopher John Kenney: As a reminder, we intend to submit an NDA upon the successful completion of extra all to our first axiom 11 of one phase III clinical trial, along with the existing data package from our phase two B X tole clinical trial and additional safety data from other clinical trials to meet regulatory requirements.

Christopher John Kenney: Turning now to our work in major depressive disorder, and as Ian indicated in his comments, we believe the ex Nova results were compelling and supportive of continued clinical development of <unk> 11 O. One N M. D D to summarize the findings from ex Nova ex CN 11, O one demonstrated clinically meaningful and dose dependent.

Christopher John Kenney: And activity in depression, and anhedonia, although we did not reach statistical significance in the trials primary endpoint of moderates there was a clinically meaningful separation of greater than three points between placebo and 20 milligrams of Exeunt 11 O. One and statistical significance was achieved on a number of important set.

Christopher John Kenney: Although we did not reach statistical significance in the trial's primary endpoint of MADH, there was a clinically meaningful separation of greater than three points between placebo and 20 milligrams of XCN-1101, and statistical significance was achieved on a number of important secondary XEN11-01 achieved statistical significance at week 6 on the Hamilton Depression Rating Scale, or HAM-D17, a scale that has been used as a primary endpoint in Phase XEN11-01 achieved statistical significance in Madras at week one, demonstrating early onset of efficacy. And XEN11-01 achieved statistical significance in reporting of at least minimally improved symptoms of depression, as assessed by physicians using the clinical global impression approach.

Christopher John Kenney: Kundera endpoints.

Christopher John Kenney: Exeunt 11 O one achieved statistical significance at week, six and the Hamilton Depression rating scale or Ham D. 17, a scale that has been used as a primary endpoint in phase III Depression studies.

Christopher John Kenney: Ex CN 11 O one achieves statistical significance on changing the sneed Hamilton pleasure scalar shops, measuring and had donia at week six.

Christopher John Kenney: <unk> 11 O one achieves statistical significance in mantras at week, one demonstrating early onset of efficacy and.

Christopher John Kenney: And X 10, 11, a one achieves statistical significance and reporting of at least minimally improve symptoms of depression as assessed by physicians using the clinical global impression of improvement.

Christopher John Kenney: Since reporting reporting the ex Nova results in November we've made significant progress around key trial elements to position us for success in phase III.

Christopher John Kenney: Since reporting the Ex Novo results in November, we've made significant progress around key trial elements to position us for success. Broadly, our development plans include three Phase 3 clinical trials, each one with one active drug on it. In other words, 20 milligrams versus placebo, compared to Exnova, which had two active drugs.

Christopher John Kenney: Broadly our development plans include three phase III clinical trials, each one with one active drug arm in other words 20 milligrams versus placebo compared to ex Nova which had two active drug arms based on a review of the literature. We believe this should help lower the placebo response.

Christopher John Kenney: Based on our review of the literature, we believe this should help lower the placebo effect. We also intend to use the primary endpoint of HAM-D17, where we demonstrated statistical significance in Exnova, while raising the baseline HAM-D17 threshold for entry to ensure a moderate to severe MDD-Pi. We plan to assess the efficacy of Xenon 1101 compared to placebo on improvement in anhedonia using the Snaith-Hamilton Pleasure Scale, or SHAPS, and HAM-D17 at week one as key secondary endpoints with the hopes of confirming the compelling data we generated around rapidity of onset.

Christopher John Kenney: We also intend to use the primary endpoint of Ham D 17, where we demonstrated statistical significance and ex Nova while raising the baseline Ham D 17 threshold for entry to ensure a moderate to severe M. D D population.

Christopher John Kenney: We plan to assess the efficacy of <unk> 11, O one compared to placebo on improvement and anhedonia using the Snape Hamilton pleasure scalar shops, and Ham D 17 at week, one as key secondary endpoints with hopes to confirm the compelling data we generated around rapidity of onset and ex Nova.

Christopher E. Von Seggern: We intend to align with FDA on these and other key design and protocol elements at a scheduled end of phase two meeting in April. Our aim is to initiate our first phase 3 MDD study in the second half of the year. We recognize the importance of continuing to raise the profile of Xenon 1101 within the healthcare community, and we intend to continue connecting with leading physicians, epileptologists, and psychiatrists. In the coming months, our team is looking forward to further outreach at the annual meeting of the American Academy of Neurology, or AAN, which is taking place in mid-April in Denver, where we have two podium presentations highlighting XCN 1101 data from XTOL We also plan to feature our Ex Novo results at a suitable psychiatric-related scientific meeting. We are encouraged and excited by physicians' enthusiasm for Exeon 1101 and its potential to improve the lives of patients with epilepsy and depression. 2024 will be a key year of clinical execution for us with continued advancements in our phase 3 epilepsy trials in anticipation of our first phase 3 readout from XTOL2 and three phase 3 clinical I would now like to turn the call over to Chris von Seggern, who will share some of our recent findings from primary market research to further build upon our understanding of how Exeon 1101 might address some of the current unmet needs. Chris- Thanks, Chris.

Christopher John Kenney: We intend to align with the FDA on these and other key design and protocol elements. It is scheduled end of phase two meeting in April of this year.

Our aim is to initiate our first phase III <unk> study in the second half of this year, we recognize the importance of continuing to raise the profile of vaccine at 11 O. One within the health care community and we intend to continue connecting with leading physicians epileptic <unk> and psychiatrist accumulative.

Christopher John Kenney: In the coming months, our team is looking forward to further outreach at the annual meeting of the American Academy of neurology or a N, which is taking place in mid April in Denver, where we have two podium presentations highlighting exeunt 11 O. One data from X tall and data from the ongoing X Tole open label extension study.

Christopher John Kenney: We also plan to feature our ex Nova results at a suitable psychiatric related scientific Congress later this year.

Christopher John Kenney: We are encouraged and excited by physicians enthusiasm for <unk> at 11 O one and its potential to improve the lives of patients within both the epilepsy and depression communities 'twenty 'twenty four will be a key year of clinical execution for us with continued advancements in our phase III epilepsy trials in anticipation of our first phase III readout for.

Christopher John Kenney: Ex told two and three phase III clinical trials in depression.

Christopher John Kenney: I would now like to turn the call over to Chris one failure, who will share some of our recent findings from primary market research to further build upon our understanding of how exon 11 O. One might address some of the current unmet needs in depression, Chris.

Christopher John Kenney: Thanks, Chris.

Christopher E. Von Seggern: By way of background, we firmly believe that market research is an integral part of our planning process to better inform our clinical and commercial development plans. Similar to our approach in epilepsy, we are expanding our understanding of MDD based in part on our own primary market research with prescribing physicians. Based on those market research findings, we believe that, if approved, Exeon 1101 can play a significant role within the MDD treatment landscape. Digging deeper into the research, we surveyed 150 high-volume prescribing physicians, psychiatrists, and other key opinion leaders in the U.S. to test the product profile of Xenon 1101, reflective of the Ex Nova findings, to understand its fit within the current treatment paradigm. Similar to our epilepsy research, physicians were interested in a drug profile that included ease-of-use attributes, such as once-daily dosing with no titration.

Christopher John Kenney: Background, we firmly believe that market research as an integral part of our planning process to better inform our clinical and commercial development plans similar to our approach and epilepsy, we are expanding our understanding of MTT based in part on our own primary market research with prescribing physicians.

Christopher John Kenney: Based on those market research findings, we believe that if approved <unk> could play a significant role within the mgd treatment landscape.

Christopher John Kenney: Digging deeper into the research, we surveyed 150 high volume prescribing physician psychiatrist and other key opinion leaders in the U S.

Christopher John Kenney: It's a testament to <unk> product profile is excellent at 11 O. One reflective of the ex Nova findings to understand its fit within the current treatment paradigm.

Christopher John Kenney: Similar to our epilepsy research physicians were interested in the drug profile that included ease of use attributes such as once daily dosing with no titration other.

Christopher E. Von Seggern: Other key takeaways include physicians being interested in new agents with novel mechanisms of action, especially given the heterogeneity of depression and the current unmet need of those patients who do not respond initially to generic therapies such as SSRIs or SNRIs. Additionally, physicians are looking for new therapeutics that do not have the liabilities of commonly used agents such as sexual dysfunction and significant weight gain.

Christopher John Kenney: Other key takeaways include physicians are interested in new agents with novel mechanisms of action, especially given the heterogeneity of depression and the current unmet need in those patients who do not respond initially to generic therapies, such as ssris or SNRI.

Christopher John Kenney: Physicians are looking for new therapeutics that do not have liabilities of commonly used agents such as sexual dysfunction and significant weight gain.

Christopher E. Von Seggern: There is keen interest in products that have the potential to deliver rapid relief of symptoms given the delayed therapeutic response with the current standard of care. Physicians also identified the ability to address anhedonia, a common comorbidity of depression, as another potential differentiator. Given supported preclinical research and statistically significant results from our Ex Nova study, when evaluating a secondary anhedonia endpoint using the SHOP scale, this presented another dimension of keen interest in XEN 1101. These survey results are highly encouraging of a compelling product fit for Axion 1101 in the future MDD treatment landscape. Further, given depression is a common comorbidity in epilepsy patients, efficacy in MDD could be a notable differentiator in epilepsy, particularly given that select anti-seizure medications are associated with unwanted mood symptoms.

Christopher John Kenney: There is keen interest in products that have the potential to deliver rapid relief of symptoms given the delayed therapeutic response with the current standard of care.

Christopher John Kenney: Physicians also identified the ability to address Antonia common core ability of depression as another potential differentiator given supported preclinical research and statistically significant results from our ex Nova study when evaluating secondary.

Christopher John Kenney: Endpoint using the shops scale. This presented another dimension of keen interest in <unk>.

Christopher John Kenney: These survey results are highly encouraging of our compelling product set for asking anti-lebanon wanted to future MDT treatment landscape.

Christopher John Kenney: Further given the depression of the common comorbidity in epilepsy patients efficacy in MTBE it could be a notable differentiator in epilepsy, particularly given the net debt select anti seizure medications are associated with unwanted mood symptoms.

Christopher John Kenney: We are incredibly excited about our strategy to pursue multiple streams of late stage clinical development of Etsy and 11, one in epilepsy and depression and based on our market research see further potential for the <unk> mechanism of Axion 11, and wanted to have even broader applicability in other neurological indications.

Christopher E. Von Seggern: We are incredibly excited about our strategy to pursue multiple streams of late-stage clinical development of XCN1101 in epilepsy and depression, and based on our market research, we see further potential for the KB7 mechanism of XCN1101 to have even broader applicability in other neurological indications. I will now turn the call over to Sherry to summarize our financial results and upcoming milestones.

Christopher John Kenney: I will now turn the call over to Sherri to summarize our financial results and upcoming milestones Sherri.

Sherry Aulin: Thanks, Chris before diving in I wanted to take a moment to introduce a new member of our team Chad <unk>, who is joining <unk> as our vice President of Investor Relations. Many of you on the call. We'll now chat as an integral member of the Investor Relations team at Sea Gen, leading up to its $40 billion buyout by Pfizer and priority Sea Gen chats that nearly two.

Sherry Aulin: Thanks, Chris. Before diving in, I wanted to take a moment to introduce a new member of our team, Chad Fugere, who is joining Xenon as our Vice President of Investor Relations. Many of you on the call will know Chad is an integral member of the Investor Relations team at Cigen, leading up to its $40 billion buyout by Pfizer. And prior to Cigen, he spent nearly two decades as a healthcare analyst on both the sell side and buy side. We're excited to welcome Chad and proud that Xenon continues to attract top talent across all areas of our business. Turning now to our financial results, Xenon is in the fortunate position of having a strong balance sheet to support our broad and robust plans for Xene 1101 and other programs in our pipeline. We're grateful for the support of existing shareholders and the additional new investors who participated in our capital raise in December following the release of our Phase 2 Ex Nova data. As of December 31, 2023, cash and cash equivalents, and marketable securities were $930.9 million compared to $720.8 million as of December 31, 2022.

Sherry Aulin: Two decades as a health care analyst on both the sell side and buy side. We're excited to welcome Chad and proud that the non continues to attract top talent across all areas of our business.

Turning now to our financial results Dino and is in a fortunate position of having a strong balance sheet to support our broad and robust plans for <unk> hundred one and other programs in our pipeline.

Sherry Aulin: We're grateful for the support of existing shareholders and the additional new investors who participated in our capital raise in December following the release of our phase two <unk> data.

Sherry Aulin: As of December 31st 2023, cash and cash equivalents in marketable securities were $930 9 million compared to $720 8 million as of December 31, 2020, Q bolstered by this recent financing round, we have extended our cash runway into 2027, which is based on current operating plan.

Sherry Aulin: <unk> that include our Ixia and 11 O one phase III epilepsy studies and fully supporting late stage clinical development of <unk> 11 O. One an M. D D, which includes three planned phase III clinical trials I would refer you to our news release and 10-K report for further details around our financial results.

Sherry Aulin: Looking ahead to some important milestone events raising on this year well continue to focus on advancing our <unk> 11 O. One phase III epilepsy program, including our <unk> X Tole, three clinical trials and fos and our exact clinical trial in PG Tcs with patient enrollment and ex told to you expected to complete in late 2024.

Sherry Aulin: Bolstered by this recent financing round, we have extended our cash runway into 2027, which is based on current operating plans that include our Xeon 1101 Phase III epilepsy studies and fully supporting late-stage clinical development of Xeon 1101 and MDD, which includes three planned Phase III clinical trials. I would refer you to our news release and 10-K report for further details on our financial results. Looking ahead to some important milestone events for Xenon this year, we'll continue to focus on advancing our XCN 1101 Phase 3 epilepsy program, including our XTOL 2 and XTOL 3 clinical trials in FOS and our exact clinical trial in PGTCS, with patient enrollment in XTOL 2 expected to complete in late 2024 to early 2025. We anticipate participating in an end of phase 2 meeting with FDA in the We expect to conduct 3 Phase 3 clinical trials in MDD, with the 1st study expected to start in the 2nd half of this year.

Sherry Aulin: Hard to early 2025, we anticipate participating in an end of phase two meeting with FDA in the second quarter of this year to align on elements of the design and protocol for our phase III <unk> 11 O. One clinical program and M. D. D. We expect to conduct three phase III clinical trials and M. D D with the first study expected to.

Sherry Aulin: Initiate in the second half of this year, we can continue to explore potential opportunities for etsy and 11 O. One in other indications and finally, we intend to advance our early stage preclinical ion channel programs with the goal of delivering.

Sherry Aulin: The goal of having multiple candidates enter IND, enabling studies.

Sherry Aulin: Both this year and next year I hope our call today are conveying the sense of excitement and anticipation we have as a team around <unk> 11 O one and dean on other promising early stage programs based on its unique mechanism of action and attractive product profile, we see immense opportunity for Etsy, and 11 O one in epilepsy depression and potentially other <unk>.

Sherry Aulin: Indications, we believe that our depth of experience in ion channel drug discovery and development will help us continue to advance and grow our robust product pipeline I'll now ask the operator to open the line for any questions.

Sherry Aulin: And finally, we intend to advance our early stage preclinical ion channel programs with the goal of delivering or the goal of having multiple candidates enter IND enabling studies, both this year and next year. I hope our call today has conveyed the sense of excitement and anticipation we have as a team around Exxon 1101 and Xenon's other promising early-stage programs. Based on its unique mechanism of action and attractive product profile, we see immense opportunity for Exxon 1101 in epilepsy, depression, and potentially other indications.

Speaker Change: If you would like to ask a question press star followed by the number one on your telephone keypad, we ask that you limit to one question and one follow up and reenter the queue for further questions first.

Speaker Change: First question comes from the line of Paul with Stifel. Your line is open.

Paul: Thanks, So much for taking my question and congrats on the progress I was wondering if you can give a little bit more color on what you're seeing at the site level as it relates to enrollment in X Tole Q.

Paul: And whether things are running a little bit slower than planned recently or if theres any kind of context, you can give around the updated timing guidance and then as it relates to be NAV. One seven program given the buzz in pain I was just curious if you could kind of drill down there. How confident are you that you have a compelling lead candidate and when do you think something like that could be in the clinic.

Sherry Aulin: We believe that our depth of experience in ion channel drug discovery and development will help us continue to advance and grow a robust product pipeline. I'll now ask the operator to open the line for any questions. If you would like to ask a question, press star followed by the number one on your telephone keypad.

Speaker Change: Thanks, so much.

Speaker Change: Thanks, Paul I can address those comments and then colleagues can jump in as well so specifically on export too so it probably just good.

Speaker Change: Level set and add a little bit of a reminder, both as we think about ex all the phase II program, obviously that we executed on a few years ago.

Operator: We ask that you limit yourself to one question and one follow-up and re-enter the queue for further questions. Your first question comes from the line of Paul Matteis with CFL. Your line is open. Hey, thanks so much for taking my question, and congrats on the progress. I was wondering if you could give a little bit more color on what you're seeing at the site level as it relates to enrollment in XTOL 2 and whether things are running a little bit slower than planned recently, or if there's any kind of context you can give around the updated timing guidance. And then, as it relates to the NAV 1.7 program, given the buzz and pain, I was just curious if you could kind of How confident are you that you have a compelling lead candidate, and when do you think something like that could be in the clinic? Thanks so much.

Speaker Change: 325 subjects and then if we think about <unk> and <unk> three 360 subjects to get these studies completed takes about 80 to 100 medical centers.

Speaker Change: I know you know, but just to be clear for everybody on the call. We go to multiple jurisdictions, where not just in North America, but in many countries in Europe as well and so just given those dynamics you just have a little bit of natural kind of ebb and flow as we think about screening as well as randomization is on a site by site basis. So there's nothing specific to answer your.

Speaker Change: That we're seeing so today's refined guidance is just an update based on the best information and modeling that we have today.

Ian C. Mortimer: Thanks, Paul. I can address those comments, and then my colleagues can jump in as well. So, specifically on XTOL-2, so probably just good to level set and have a little bit of a reminder, both as we think about XTOL, the Phase 2 program, obviously, that we executed on a few years ago, 325 subjects, and then if we think about XTOL-2 and XTOL-3, 360 subjects. To get these studies completed takes about 80 to 100 medical centers, as I know you know, We're not just in North America but in many countries in Europe as well.

Speaker Change: If we think about NAV, one seven yes, I think youre kind of getting a feel of kind of our excitement around this program and obviously, we've been working in NAV one seven for many many years from as I mentioned in the prepared remarks, we are the first to climb the gene the SCN nine aging many many years ago and then we've been on.

Working on Chemistries.

Speaker Change: So probably 15 plus years on the target.

Speaker Change: I think we have some really advanced candidates internally than me from our perspective, all of the requirements for development and obviously, where we have a significant number of criteria that we worked through both in terms of kind of efficacy and potency on target, but as well as pharmaceutical properties and therapeutic index that we would expect so.

Ian C. Mortimer: And so, given those dynamics, you just have a little bit of natural ebb and flow as we think about screening, as well as randomization on a site-by-site basis. So, there's nothing specific, you know, to answer your question that we're seeing. So today's refined guidance is just an update based on the best information and modeling that we have today. If we think about NAV1.7, yeah, I think you're kind of getting a feel for our excitement around this program, and obviously, we've been working on NAV1.7 for many, many years. As I mentioned in my prepared remarks, we were the first to clone the gene, the SCN9A gene, many, many years ago, and then we've been working on chemistry for probably 15 plus years on the target.

Speaker Change: We're continuing to do that preclinical work and as I mentioned I think we're going to see multiple candidates move into IND, enabling studies over the next couple of years and then as I mentioned nice thing as you know about pain as we can do these early proof of concept studies in human as well.

Speaker Change: Thank you.

Speaker Change: Thanks.

Speaker Change: Your next question comes from the line of Brian Abrahams from RBC capital markets. Your line is open.

Speaker Change: Hi, guys. This is leonid on for Brian Thanks for taking our question.

Leonid: I wanted to ask on M D D and specifically on the investigator initiated study I guess curious if you guys feel like you have everything you need.

Ian C. Mortimer: I think we have some really advanced candidates internally that meet, from our perspective, all of the requirements for development, and obviously, we have a significant number of criteria that we work through, both in terms of kind of efficacy and potency on target, but as well as pharmaceutical properties and therapeutic index that we would expect. So we're continuing to do that preclinical work, and as I mentioned, I think we're going to see multiple candidates move into high-end enabling studies over the next couple of years, and then, as I mentioned, the nice thing, as you know about pain, is we can do these early proof of concept studies in humans as well. Thank you. Thanks. Your next question comes from the line of Brian Abrahams from RBC Capital Markets. Your line is open. Hi guys. This is Leonid on for Brian.

Leonid: To plan your MTBE trials based upon your own work or if there's anything specific you're looking for from the investigator initiated trial and if you think you'll have some of that data in hand as you go to the FDA to discuss the trial design to have the end of phase two meeting thanks.

Leonid: Yeah.

Speaker Change: Sure. Thanks Lynette.

Chris why don't I give my comments and then jump in maybe as you think about the end of phase two meeting.

Speaker Change: Paul with the agency. So there's nothing specific we are looking for from the ISP.

Speaker Change: We weren't really informed by the ex Nova study, obviously with a company sponsored study larger number of sites. It was a larger study.

Paul: The Mount Sinai Baylor studies, so really that was our focus in terms of critical information for decision, making purposes and what you heard today is we're committed to late stage development and we're committed to doing three phase III clinical trials in Mds, but Chris anything to add as we think about just going into the end of phase two minutes.

Christopher John Kenney: Thanks for taking our question. I wanted to ask about MDD and specifically about the investigator-initiated study. I'm curious if you guys feel like you have everything you need to plan your MDD trials based on your own work or if there's anything specific you're looking for from the investigator-initiated trial and if you think you'll have some of that data in hand as you go to the FDA to discuss trial design and have the end of Phase II meeting. Thanks. Sure. Thanks, Leonid.

Christopher John Kenney: Well just a brief comment on the on the investigator initiated trials and more time spent on getting to transitioning from phase II to phase III. So the investigator initiated trial there isn't anything that we need from there to be prepared for the end of phase two meeting I think.

Christopher John Kenney: The one interesting part about that study is that it includes functional MRI and what it will do is sort of give some insight into the antidepressant effects that we saw in terms of what is the actual underlying mechanisms. So theres been this theory that there is a population of neurons that are hyper excitable that project up to the nucleus accumbens.

Christopher John Kenney: Chris, why don't I give my comments and then jump in maybe as you think about the end of Phase 2 meeting in April with the agency. So there's nothing specific we're looking for from the IST. I think we were really informed by the Ex Nova study, obviously, with a company-sponsored study, a larger number of sites. It was a larger study than the Mount Sinai Baylor study.

Christopher John Kenney: <unk> and MRI will sort of get to the bond with that so I think it will answer a fairly academic.

Speaker Change: Interesting, but academic question about the mechanism. How these these drugs with <unk> seven can improve depression, but it isn't needed.

Speaker Change: We have everything we need we've been going through this data with a fine tooth comb and doing everything we can to understand it and you know largely keep continue the things that worked and refine the things that we think can improve our chance of success like decreasing them two active arms down to one that usually improves the placebo.

Christopher John Kenney: So, really, that was our focus in terms of critical information for decision-making purposes. And what you heard today is that we're committed to late stage development, and we're committed to doing three Phase 3 clinical trials in MDD. But Chris, anything to add as we think about just going into the end of phase 2 meeting? Well, just a brief comment on the investigator-initiated trial and then more time spent on getting to transitioning from phase 2 to phase 3. So the investigator-initiated trial, there isn't anything that we need from there to be prepared for the end of phase 2 meeting.

Speaker Change: Good point or so so we're we're ready to go we have everything we need the I S. T study is not gating whatsoever.

Speaker Change: Got it thanks.

Speaker Change: Yeah.

Speaker Change: Yeah.

Speaker Change: Your next question comes from the line of Jason <unk> with Bank of America.

Christopher John Kenney: I think the one interesting part about that study is that it includes functional MRI. And what it will do is sort of give some insight into the antidepressant effects that we saw in terms of what the actual underlying mechanism is. So there's this theory that there's a population of neurons that are hyper excitable that project up to the nucleus accumbens.

Speaker Change: Hi, Good evening. This is Dana on for Jason. Thanks for taking our question. We just had one on M. D D mine.

Dana: Mindful that youre waiting FDA feedback just wanted to kind of get your thoughts on what you're focusing on in terms of planning a successful.

Dana: That said program I guess specifically.

Christopher John Kenney: And the fMRI will sort of get to the bottom of that, so I think it will answer a fairly interesting but academic question about the mechanism, how these drugs with KV7 can improve depression. We have everything we need.

Dana: Curious, how you're thinking about balancing potentially pushing dose to 25, no ground to get a better dose response and hit stat Sig on mattress.

Christopher John Kenney: We've been going through this data with a fine tooth comb and doing everything we can to understand it and largely continue the things that worked and refine the things that we think can improve our chance of success. Like, you know, decreasing two active arms down to one usually improves the placebo effect by a good point or so. So we're ready to go. We have everything we need. The IST study is not gating whatsoever.

Dana: But potentially giving up a little bit on tolerability.

Dana: Knowing that bio havens KD seven that has demonstrated a really clean safety profile is also entering mbd trials. Thank you.

Speaker Change: Thanks Dana.

Speaker Change: Why don't we Chris Kenny lets why don't you focus on dose selection and obviously.

Christopher John Kenney: That's about it. Thanks. Your next question comes from the line of Jason Gerberry with Bank of America. Your line is open. Hi, good evening. This is Dina on behalf of Jason.

Speaker Change: Deanna mentioned, Matt dress, but obviously, we're moving says IMD 17, so maybe kind of walk through.

Christopher John Kenney: A little bit of our thinking around dose selection.

Operator: Thanks for taking our question. We just had one on MDD. Mindful that you're waiting for FDA feedback, just wanted to kind of get your thoughts on what you're focusing on in terms of planning a successful STATFIG program. I guess specifically, Curious how you're thinking about balancing potentially pushing the dose to 25mg to get a better dose response and hit StatSig on Modris but potentially giving up a little bit on tolerability, just knowing that BioHaven's KB7, which has demonstrated a really clean safety profile, is also entering MVD trials. Thanks, Dina.

Christopher John Kenney: The endpoints and then Chris one CAGR I think it'd be helpful. Just to provide you know we've done a lot of market research, we shared a little bit Oss today, but really thinking about what the drivers are here as we think about that trade off between efficacy and tolerability.

Christopher John Kenney: Yeah.

Christopher John Kenney: Yeah sure. So I mean, I think in terms of the two things that are going to increase our chance of success. Even further as we go from phase II to phase III I would say decreasing the active dose arms from from two to one as one and the other what Ian just said, which is switching the primary endpoint for modules to M. D. C 17.

Christopher John Kenney: So the Ham D 17 was statistically significant in ex Nova that's largely driven by the fact that there was less variability and we've seen that in other Mtv's study. So those are the two big things that I think will increase our chances of success, we've had quite a bit of internal debate about the appropriate dose going forward into phase III.

Christopher John Kenney: Why don't we, Chris, Kenny, let's, why don't you focus on dose selection and obviously the, you know, Dina mentioned Madras, but obviously we're moving to the HANP D17, so maybe kind of walk through a little bit of our thinking around dose selection and the endpoints. And then Chris von Seggern, I think it'd be helpful just to provide, you know, we've We shared a little bit of it today, but I'm really thinking about what the drivers are here as we think about that tradeoff between efficacy and tolerability. Yeah, sure.

Christopher John Kenney: It was pretty easy for 20 milligrams to win out over 10 milligrams as you take a look at the efficacy endpoints, both both depression skills and Anne had donia and the clinical global impression of change and then to the debate about 'twenty versus 25, I think is more nuanced, but I think that if you look at the totality of the data.

Christopher John Kenney: From the epilepsy program, which is that sure. There is an increase in efficacy as you go from 'twenty to 'twenty five but also there was a slight increase in adverse events.

Christopher John Kenney: Particularly the most common one of dizziness, and so forth, we think that based upon the market research, which which Chris will speak to the largely indicates that safety is a large driver for patient starting and staying on medications. We think that overall the benefit of sticking with 20 milligrams outweighs the possibility of going forward with.

Christopher John Kenney: So I mean, I think in terms of the two things that are going to increase our chance of success. So the HAM-D17 was statistically significant in ex-nova. That's largely driven by the fact that there was less variability, and we've seen that in other MDD studies. So those are the two big things that I think will increase our chance of success. We've had quite a bit of internal debate about the appropriate dose going forward into phase three. It was pretty easy for 20 milligrams to win out over 10 milligrams as you take a look at the efficacy endpoints, both depression scales and anhedonia, and the clinical global impression of change. But then the debate about 20 versus 25, I think, is more nuanced.

Christopher John Kenney: With 25.

Christopher John Kenney: I think I'll leave it at that we're pretty happy with ex Nova we particularly in terms of the dose the reaction that 20 milligrams had on efficacy and safety keep in mind that the safety appeared to be even better and the M. D D than it was a focal onset seizures.

Speaker Change: So we're going to go forward with 20, Chris.

Christopher John Kenney: [music].

Speaker Change: What maybe maybe just to add to what Chris said.

Speaker Change: I think when we look at the data it stemming from ex Nova and we translate that into.

Speaker Change: A product profile that has been shared with physicians.

Speaker Change: Clinically meaningful separation, we saw against the endpoints with resonated really well with physicians and importantly, when you translate that or compare it against what physicians are used to seeing for the products. There that have been approved in the marketplace today.

Christopher John Kenney: But I think that if you look at the totality of the data from the epilepsy program, which is that sure, there is an increase in efficacy as you go from 20 to 25, but there was also a slight increase in adverse events, particularly the most common one of dizziness, and so forth. We think that based on market research, which Chris will speak to, that safety is a large driver for patients starting and staying on medication. We think that overall, the benefit of sticking with 20 milligrams outweighs the possibility of going forward with 25, and... I think I'll leave it at that. We're pretty happy with Exnova. Thank you very much for joining us today. We're going to go forward with 20. Chris?

Speaker Change: There isn't meaningful separation.

Speaker Change: As a result, what we heard and this was quite consistent across the the nature of the research. We've done to date is that this is not an efficacy driven market. So maybe ill share it a little bit differently efficacy is defined by products that are FDA approved and the ability to prove to poll for a product that has a quota.

Speaker Change: Higher benefit on <unk> is not something that physicians identified as a key unmet need instead, what they're pointing to are things such as.

Speaker Change: Adverse spend profiles safety and Tolerability as primary drivers of decision, making and what we've heard very consistently in our market research is novel mechanism of action with a safety and Tolerability profile that as Chris had mentioned was actually quite favorable when compared to the epilepsy profile really resonated well.

Christopher John Kenney: Maybe just to add to what Chris said, I think when we look at the data stemming from Ex Novo and translate that into a product profile that has been shared with physicians, the clinically meaningful separation we saw against the endpoints resonated really well with physicians. And importantly, when you translate that or compare it against what physicians are used to seeing for the products that have been approved in the marketplace today, there isn't any meaningful separation. And as a result, what we heard, and this was quite consistent across the nature of the research we've done to date, is that this is not an efficacy-driven market. So maybe I'll share it a little bit differently.

That's a big part of the rationale in our thinking heading into why we feel really confident in the 20 milligram.

Speaker Change: Our selection.

Speaker Change: Thank you very much.

Speaker Change: Your next question comes from the line of Tessa Romero with Jpmorgan. Your line is open.

Speaker Change: Yeah.

Tessa Thomas Romero: Good afternoon, guys. Thanks for taking our questions.

Christopher E. Von Seggern: Efficacy is defined by products that are FDA-approved, and the ability to pull for a product that has a, quote-unquote, higher benefit on Modris is not something that physicians identified as a key unmet need. Instead, what they're pointing to are things such as adverse event profiles, safety, and tolerability as primary drivers of decision-making. And what we've heard very consistently in our market research is a novel mechanism of action with a safety and tolerability profile that, as Chris has mentioned, was actually quite favorable when compared to the epilepsy profile really resonated well. And that's a big part of the rationale in our thinking heading into why we feel really confident in the 20-milligram selection. Your next question comes from the line of Tess Romero with J.P. Morgan. Your line is open.

Tessa Thomas Romero: First one is you gave us a little bit of color Tonight on external to enrollment.

Tessa Thomas Romero: Thanks, Zach enrollment going and do you think you might be a position to guide.

Tessa Thomas Romero: <unk> sometime this year and then second question is just as a follow up to some of your earlier comments are you able to give us any further detail and what the next update might be from you on your discovery programs.

Tessa Thomas Romero: NAV, one one and one seven.

We see something further from you all before in <unk>, how should we be thinking about that thanks.

Speaker Change: Yes, I'm happy to address both of those questions.

Speaker Change: Yes, just as a reminder, you asked about exact so I think most people know, but we've got two focal epilepsy studies going on XL to an extra three in that exact is the primary generalized tonic clonic seizure study so both for export III and exact.

Operator: Good afternoon, guys. Thanks for taking our questions. The first one is, you gave us a little bit of color tonight on EXTOL 2 enrollment. How is exact enrollment going?

Speaker Change: Haven't yet given enrollment guidance, but that is something that we'll do in the future I think most important we really are focused on X tole too because as we keep talking about that's on the critical path to filing the NDA and the potential approval of <unk> hundred one in terms of exact depending on the timing of exact doctor either be.

Ian C. Mortimer: And do you think you might be in a position to guide for enrollment completion sometime this year? And then, secondly, as a follow-up to some of your earlier comments, are you able to give us any further detail on what the next update might be from you on your discovery programs on NAV 1.1 and NAV 1.7? Could we see something further from you all before an IMD? How should we be thinking about that? Thanks. Thanks, Tess.

Speaker Change: Part of the basis of the NDA or it could be a supplemental application and from our perspective I'm not sure it really matters that much because prior to launch even in Sos. We know that we'll have the PGE Tcs data available and then obviously, we can follow up with regulators thereafter.

Ian C. Mortimer: Yeah, I'm happy to address both of those questions. So, yeah, just as a reminder, you asked about XACT. So, I think most people know, but we've got two focal epilepsy studies going on, X-Poll 2 and X-Poll 3, and then XACT is the primary generalized tonic-clonic seizure study, so both for X-Poll 3 and XACT. We haven't yet given enrollment guidance, but that is something that we'll do in the future. But, most importantly, we really have focused on X-Poll 2 because, as we keep talking about, that's on the critical path to filing the NDA and the potential approval of XCN 1101. In terms of XACT, depending on the timing of XACT, that could either be part of the basis of the NDA, or it could be a supplemental application.

Speaker Change: So obviously there is a huge amount of laser focus on X tole too.

Speaker Change: In <unk> III, an exact are important and we'll give guidance as we move forward.

Speaker Change: On your discovery question, Yes, I think Theres a couple of a couple of opportunities for us to give some updates you referenced in the question specifically NAV, one one and one seven and I don't want to lose that we've also got a very broad program in <unk>, because we do believe.

Ian C. Mortimer: And from our perspective, I'm not sure it really matters that much because prior to launch, even in FOS, we know that we'll have the PGTCS data available, and then obviously, we can follow up with regulators thereafter. So, obviously, there's a huge amount of laser focus on X-Poll 2 and X-Poll 3, and XACT is important, and we'll give guidance as we move forward. On your discovery question, yeah, I think there's a couple of opportunities for us to give some updates. You referenced NAV 1.1 and 1.7 in your question specifically, and I don't want to lose that we've also got a very broad program in KV, because we do believe that the mechanism is well validated, both in epilepsy, obviously, with our XTOL data, and in psychiatric conditions with our So there's really an opportunity to have this broad leadership role in KV7.

Speaker Change: That the mechanism is well validated both in epilepsy, obviously with our <unk> data and in psychiatric conditions with our ex Nova data, there's really an opportunity to have this broad leadership role in <unk> seven so you'll hear more from us.

Speaker Change: On some of those molecules as well and actually those are the most advanced molecules. If we think about our entire discovery portfolio.

Speaker Change: Specifically on <unk>, one we have shared some data on 1.1, if you go back to the American Epilepsy Society meetings over the last couple of years, we've been providing some of our preclinical and animal data at.

Speaker Change: At the epilepsy meeting so do go to our website and you can you can find those posters and I think there's some really compelling data there.

Speaker Change: There's always an opportunity for us to continue to provide updates as we go forward and then was not one seven we haven't shared any of our data publicly so that would be the opportunity as we move forward not only updates on where we are in terms of IND, enabling studies and getting close to an IND or Cta filing and first in human studies, but.

Ian C. Mortimer: So you'll hear more from us on some of those molecules as well. And actually, those are the most advanced molecules if we think about our entire discovery portfolio. Specifically, on NAV1.1, we have shared some data on 1.1. If you go back to the American Epilepsy Society meetings over the last couple of years, we've been providing some of our preclinical and animal data at the epilepsy meetings. So do go to our website, and you can find those posters.

Speaker Change: Also be able to provide some of the data that we've generated pretty clinically.

Speaker Change: The public domain at the appropriate conference. So I think those are things to look forward to over the next few years.

Ian C. Mortimer: And I think there's some really compelling data there. So there's always an opportunity for us to continue to provide updates as we go forward. And then, with NAV1.7, we haven't shared any of our data publicly.

Speaker Change: Great. Thanks for taking my questions.

Speaker Change: Thank you.

Speaker Change: Your next question comes from the line of Andrew <unk> with Jefferies. Your line is open.

Andrew: Hey, Thanks, good afternoon, thanks for taking our questions. So.

Ian C. Mortimer: So that would be the opportunity, as we move forward, not only to update you on where we are in terms of IND enabling studies and getting close to an IND or a CTA filing and first in human studies, but also to be able to provide some of the data that we've generated preclinically into the public domain at the appropriate conference. So I think those are things to look forward to over the next few years. Great. Thanks for taking our questions. Thank you. Your next question comes from the line of Andrew Tse with Jefferies. Your line is open. Hey, thanks. Good afternoon,

Andrew: Maybe the first one just in the upcoming FDA meeting in April Thanks for sharing some of the planned elements of the MDT study designs.

Andrew: Is there an upside scenario in this meeting that you're hoping for and then secondly, actually on the NAV one seven obviously theres a little buzz with NAV one eight going on so can you talk about whether you believe one seven is a superior target to one eight.

Andrew: And what do you have in some of the historical challenges and pitfalls when pursuing NAV. One seven that you think you can overcome thank you.

Operator: Thanks for taking our questions. So, maybe the first one, just at the upcoming FDA meeting in April, thanks for sharing some of the planned elements of the MDD study designs. Is there an upside scenario at this meeting that you're hoping for? And then secondly, actually, on NAV 1.7. Obviously, there's a little buzz with NAV 1.8 going on.

Andrew: <unk>.

Speaker Change: Great. Thanks, Andrew I'm happy to give some perspective on NAV, one seven and then Chris I'll pass it over to you. If you just want to provide your comments on the end of phase two meeting.

Speaker Change: And depression.

Speaker Change: So in terms of NAV, one seven Andrew.

Ian C. Mortimer: So, can you talk about whether you believe 1.7 is a superior target to 1.8? And what have been some of the historical challenges and pitfalls when pursuing NAV 1.7 that you think you can overcome? Thank you. Great. Thanks, Andrew.

Speaker Change: Andrew I think both NAV, one eight and $1 seven are well validated targets for different reasons I don't think the genetic validation is a bit stronger on NAV one seven.

Speaker Change: But we now have clinical data available that are selective.

Speaker Change: Our selective sodium channel approach inhibition approach that underground <unk> can can yield really promising.

Ian C. Mortimer: I'm happy to give some perspective on NAV1.7. And then, Chris, I'll pass it over to you if you just want to provide your comments on the end of Phase 2 meeting in depression. So in terms of NAV1.7, Andrew, I think both NAV1.8 and 1.7 are well-validated targets for different reasons. I think the genetic validation is a bit stronger on NAV1.7.

Speaker Change: <unk> efficacy data and so I think we're kind of in this really unique position, where we can leverage everything we know about 107, which we think is an extremely well validated targets genetically but feel comfortable that the selective sodium channel inhibition approach.

Speaker Change: And have <unk> therapeutic utility in the clinic.

Speaker Change: In terms of what we've learned so we had taken molecules into the clinic previously.

Speaker Change: The collaboration with Genentech, and we're going back to.

Ian C. Mortimer: But we now have clinical data available that a selective sodium channel inhibition approach, specifically on 1.8, can yield really promising human efficacy data. And so I think we're kind of in this really unique position where we can leverage everything we know about 1.7, which we think is an extremely well-validated target genetically, but feel comfortable that this selective sodium channel inhibition approach can have therapeutic utility in the clinic. In terms of what we've learned, so we had taken molecules into the clinic previously in a collaboration with Genentech, and we're going back kind of to the 2015 range when we moved some of those molecules ahead with Genentech. I think we've learned a lot about both the chemistry and the distribution of the molecules that we're leveraging to make the necessary adjustments and changes and learnings from all of that work as we think about our current So I think there's been a huge amount of learning in the field broadly as well as specifically here at Xenon that we can put into practice as we move these molecules forward.

Speaker Change: The 2015.

Range of when we have moved some of those molecules.

Speaker Change: With <unk> I think we've learned a lot about both the chemistries and the distribution of the molecules that we're leveraging to make the necessary adjustments and changes and learnings from all of that work as we think about our current chemistries in the molecules that wed like to move ahead. So I think theres been a huge amount of learning.

Speaker Change: In the in the field broadly as well as specifically here at xenon that we can put into practice as we move these molecules forward.

Christopher John Kenney: Chris on the.

Christopher John Kenney: MDM to phase two.

Christopher John Kenney: Yeah. So I mean keep in mind that we just had an end of phase two meeting in epilepsy, two years ago, and so we learned a lot about what FDA thought regarding the non clinical program clinical pharmacology safety assessments, and so forth and so the list of questions that we have going into this into phase two.

Christopher John Kenney: Two is shorter and is completely focused on major depressive disorder.

Christopher John Kenney: Within M D D. The regulatory path is pretty well trodden so.

Christopher John Kenney: The the guidance.

Christopher John Kenney: States that you can use modules or Ham D for the primary endpoint, we're choosing Ham D.

Christopher John Kenney: Chris, on the MDD end of phase 2 meeting? Yeah, so, I mean, keep in mind that we just had an end-of-phase-2 meeting in epilepsy two years ago, and so we learned a lot about what FDA thought regarding the non-clinical program, clinical pharmacology, safety assessments, and so forth. And so the list of questions that we have going into this end-of-phase-2 is shorter and is completely focused on major depressive disorder. Within MDD, the regulatory path is pretty well-trodden, so, you know, the guidance states that you can use Madras or HamD for the primary endpoint, and we're choosing HamD. We think that the clinical data and the unmet need that Chris von Segern mentioned, you know, from our research, all justifies 20 milligrams, along with some PK-PD modeling that we did as well. So there isn't anything that we're doing that's really... It is unusual.

Christopher John Kenney: We think that the clinical data and the unmet need that Chris one Seeger and <unk>.

Christopher John Kenney: You mentioned you know from our research all justifies 20 milligrams, along with some PK PD modeling that we did as well so there isn't anything that we're doing that's really.

Christopher John Kenney: Unusuals, so to your point about upside I suppose the only thing that comes to mind is we're quite interested and demonstrating improvements early on we had this efficacy signal at week, one and both focal onset seizures and in the major depressive disorder. So this seems theres a consistency there.

Christopher John Kenney: Two therapeutic areas and so I think one question is what can we do to set up the statistical hierarchy to to put ourselves in a position where that could end up in the label and then I would say the same thing for anhedonia, we're quite interested in the signal that we're seeing in terms of improvements in <unk>. We think this is really relevant.

Christopher John Kenney: So to your point about upside, I suppose the only thing that comes to mind is we're quite interested in demonstrating improvements early on. We had this efficacy signal at week one in both focal onset seizures and in major depressive disorders. So it seems there's a consistency there across two therapeutic areas. And so I think one question is, what can we do to set up a statistical hierarchy to put ourselves in a position where that could end up on the label? And then I would say the same thing about anhedonia.

Christopher John Kenney: Based upon talking to psychiatrists and the market research that Chris one Seeger and has done and so what can we do to assess those endpoints and get them in the label I think that those will be a couple of things that we talked about ultimately of course, that's going to be are there going to be review issues and so we're unlikely to get a definitive answer, but hopefully will setup tee up those conversations down the raw.

Christopher John Kenney: Good.

Speaker Change: Thanks, so much.

Yeah.

Speaker Change: Your next question comes from the line of Paul Choi with Goldman Sachs. Your line is open.

Robert: Hi, This is Robert.

Robert: Thanks for taking our questions.

Robert: Okay.

Christopher John Kenney: We're quite interested in the signal that we're seeing in terms of improvements in anhedonia. We think this is really relevant, based on talking to psychiatrists and the market research that Chris von Segern has done. And so, what can we do to assess those endpoints and get them in the label? I think those will be a couple of things that we talk about. Ultimately, of course, they're going to be review issues, and so we're unlikely to get a definitive answer, but hopefully, we'll tie up those conversations down the road. Thanks so much.

Speaker Change: What's that you can do to maintain.

Speaker Change: Thanks, a lot.

Great.

Speaker Change: Seven.

Speaker Change: They now have 1000, okay, but nobody thinks that fast.

Speaker Change: Experts.

Speaker Change: Do you think that next generation molecules, you liking, what Georgia payment strategy.

Speaker Change: I'd say, there aren't adding partnerships so much.

Speaker Change: Thanks can you just repeat the question on X tole too as it.

Operator: Your next question comes from the line of Paul Choi with Goldman Sachs. Your line is open. Hi, this is Robert.

Speaker Change: It was a question just around on whether enrollment could pick up is that correct.

Speaker Change: Yeah sure so yeah kind of.

Operator: Thanks for taking our questions. We have two. The first one is on Expo 2.

And what kind of stats that you would need to do to.

Operator: What you can do to maintain the enrollment rate or maybe, and the 7 plus 3 is the MAB 1.7. So given the recent success in this area, with your expertise, what do you think the next generation molecule should look like? And what's your design and strategy?

Speaker Change: It maintains that no woman faced or maybe eight.

Speaker Change: Yeah, I mean as I as I said in my.

Speaker Change: And the answer to the first question.

Speaker Change: On the Q&A today is.

Speaker Change: <unk>, we have there.

Speaker Change: The study is designed for 360 subjects across three arms to achieve that enrollment over an appropriate period of time. It takes about 80 to 100 medical centers and so if you just kind of do that math I think you can kind of recognize that.

Operator: Like, is it already in partnerships? Thanks. Can you just repeat the question about XTOL 2?

Operator: It was a question just around about whether enrollment could pick up, is that correct? Uh, yeah, sure. So, uh, yeah, kind of like that.

Ian C. Mortimer: And what kind of steps do you need to do in order to maintain the enrollment pace or maybe even on Saturday? Yeah, I mean, as I said, in my answer to the first question on the q&A today is, you know, in x02, we have, The study is designed for 360 subjects across three arms. To achieve that enrollment over an appropriate period of time, it takes about 80 to 100 medical centers.

Speaker Change: Each center on average brings a handful of patients into the study and so I think it's less around kind of the acceleration, but just more we just see some natural kind of ebb and flow of the screening rate, which then goes down the funnel in terms of the number of patients that go into their baseline and then eventually get randomized so I don't think.

Ian C. Mortimer: And so if you just kind of do that math, I think you can kind of recognize that each center brings a handful of patients into the study. And so I think it's less around kind of the acceleration, but we just see some natural kind of ebb and flow of the screening rate, which then, you know, goes down the funnel in terms of the number of patients that go into baseline and then eventually get randomized. So I don't think that, from our perspective, there are any adjustments that are really necessary from an xTol2 perspective. And then your question on NAV1.7 was more around partnering and future development. Was that right?

Speaker Change: From our perspective, there is no adjustments that are really necessary for.

Speaker Change: From an ex told two perspective.

Speaker Change: And then your question on NAV, one seven was more around.

Speaker Change: Around partnering and future development was that right.

Speaker Change: That's right.

Speaker Change: Yes, yes, so it's early days I mean.

Speaker Change: As we've said a number of times, we're really uniquely positioned to prosecute on the target.

Speaker Change: Because we did the early genetics on it and we've also been working on developing new Chemistries on the target for many many years. So I think we're uniquely positioned to do that so there are no plans in the near term.

Ian C. Mortimer: Yeah, so it's early days. I mean, as we've said a number of times, we're really uniquely positioned to prosecute on the target. And that's because we, you know, did the early genetics on it. And we've also been working on developing new chemistry on the target for many, many years. So I think we're uniquely positioned to do that. And there are no plans in the near term to think about partnering the asset.

Speaker Change: Just think about partnering the asset this is something that we believe we can take definitely.

Into IND, enabling studies and through early development kind of the long term plan I think that's quite a ways away in terms of how we think about potentially the commercial market, but right now we have no plans on thinking about partnering NAV, one seven really doing all of the all of the development over the next number of years by ourselves.

Operator: This is something that we believe we can definitely take into IND enabling studies and through early development. You know, kind of the long-term plan, I think that's quite a ways away in terms of how we think about potentially the commercial market. But right now, we have no plans to think about partnering NAV1.7, really doing all of the development over the next number of years by ourselves. Your next question comes from the line of Danielle Brill with Raymond James. Your line is open.

Speaker Change: Yeah.

Speaker Change: Your next question comes from the line of Danielle Brill with Raymond James Your line is open.

Good afternoon guys.

Danielle Brill: With questions on foreseen 1101, if there is any update on the pediatric formulation and what's your current thinking up the ex U S strategy. Thank you.

Operator: Good afternoon, guys. We have questions for Z1101. If there's any update on the pediatric formulation, and what's your current thinking on the XUS strategy? Thank you.

Danielle Brill: Yeah.

Speaker Change: Thanks for the questions.

Speaker Change: <unk>.

Ian C. Mortimer: Thanks for the questions. So on the pediatric formulation, why don't? I'm happy to start. And Chris Kenney, do you want to maybe just talk about how we think about kind of getting into younger age cohorts, both in FOS and then obviously the adjustments we've made in the primary generalized to get into a younger age group there? We can start there, and then I'm happy to talk about our ex-US strategy for 11.01 overall.

Speaker Change: So on the pediatric formulation.

Speaker Change: I'm happy to start and Chris Kenny do you want to maybe just talk about <unk>.

Christopher John Kenney: How we think about kind.

Christopher John Kenney: Getting into.

Younger age cohorts, both in <unk> and then obviously the adjustments we've made in the primary generalized to get them to a younger age groups there.

Christopher John Kenney: We can start there and then I'm happy to talk about.

Christopher John Kenney: Kind of our ex U S strategy for <unk> 11 O. One overall, so just kind of a couple of high level comments on pediatric before passing to crest. So yes, we are.

Christopher John Kenney: So just kind of a couple of high-level comments on pediatrics before passing to Chris. So yes, we've discussed with regulators around the pediatric plans. We have agreement on what we need to do.

Christopher John Kenney: We've discussed with regulators around the pediatric plans, we have agreement on what we need to do and Kristen and walk you through how that practically works from a development strategy point of view your specific question around a pediatric formulation. So we know that.

Christopher John Kenney: And Chris can kind of walk you through how that practically works from a development strategy point of view. Your specific question around a pediatric formulation. So we know that with an adult dosage form, that it can go down into adolescents and into children. But as we get into much younger children, we're going to need a different pediatric formulation. And that's something that we're continuing to work on at Xenon. It's not something that we have finalized.

Christopher John Kenney: With <unk>.

Speaker Change: And that'll.

Kristen: Dosage form that that can go down into adolescence and into children, but as we get into much younger children were going to need a different pediatric formulation.

Kristen: And that's something that we're continuing to work on.

Kristen: As seen on it is not something that we have finalized and so we haven't taken any other formulations into human clinical development, but that would be something that we want to do in the future, but really only as we need to get into those much younger age cohorts probably younger than age sex.

Ian C. Mortimer: And so we haven't taken any other formulations into human clinical development, but that would be something that we would do in the future, but really only as we need to get into those much younger age cohorts, probably younger than age six. But Chris, do you want to just talk through the development plan?

Kristen: Chris do you want to just talk through the development plan there.

Christopher John Kenney: Yeah, I mean, at a high level, we have agreement from both FDA and EMA in terms of the plan to bring this drug into the pediatric population as it relates to focal onset seizures with their extrapolation rules and then also with PGTCS. So there's sort of two things that have to happen before you go into those clinical trials. Ian's already mentioned, and the question mentioned the pediatric formulation.

Chris: Yes, I mean on a high level, we have agreement from both FDA and EMA in terms of the plans to bring this this drug into the pediatric population as it pertains to focal onset seizures, where they're extrapolation rules and then also with PGE Tcs. So theres sort of two things that are on that have to happen.

Chris: Before you go into those clinical trials and as already mentioned in the question mentioned the pediatric formulation. There is also some non clinical work that needs to be done and then you're then youre able to go into open label studies in pediatric patients usually starting at a higher age and then working your way down. So all of those plans have been agreed upon and are being finalized.

Christopher John Kenney: There's also some non-clinical work that needs to be done. And then you're able to go into open-label studies in pediatric patients, usually starting at a higher age and then working your way down. So all of those plans have been agreed upon and are being finalized.

Chris: And then on top of that you know already alluded to this in our P. G. T. C. S study. The exact we have brought down the age cut off from a minimum of 18 years down to 12 and so in the near future. We'll start gathering data on patients adolescent patients in terms of efficacy safety and PK and that.

Christopher John Kenney: And then on top of that, Ian already alluded to this, in our PGTCS study, the exact age cutoff from a minimum of 18 years down to 12. And so, in the near future, we'll start gathering data on adolescent patients in terms of efficacy, safety, and PK. And that will be helpful to illuminate all those plans I've already mentioned that we've discussed with EMA and FDA. So it's all ongoing. We think this drug has potential for adults and for patients, assuming that the safety profile supports it. Thanks, Chris.

Chris: <unk> will be helpful to illuminate hold those plans I already mentioned that we've discussed with EMA and FDA. So it's it's all ongoing we think this drug has potential for adults and for patients assuming that the safety profile supports it.

Speaker Change: Thanks, Chris and then the question question on kind of ex U S. What is our thinking there. So I think no real update but I'm happy to provide just our overall strategic approach there just to make sure that we're clear.

Speaker Change: So we have stated for some time that we are doing all of the development for <unk> X. Gen 11, a one currently in our plans are to build the commercial infrastructure and launch launch the drug in the U S ourselves.

Christopher John Kenney: And then the question about the kind of ex-US, what is our thinking there? So, I think, no real update, but I'm happy to provide just our overall strategic approach here, just to make sure that we're clear. So, we have stated for some time that we are doing all of the development for Xeon 1101 currently, and our plans are to build the commercial infrastructure and launch the drug in the US ourselves. But the current strategic plan is not to build that infrastructure outside of the US.

Speaker Change: But the current strategic plan is not to build that infrastructure outside of the U S. So at some point, we will be leveraging.

Speaker Change: Partners to access jurisdictions outside of the U S. Obviously, we don't guide on that timing, but.

Speaker Change: But that is something that as we think about the long term development and market access of the drugs.

Speaker Change: <unk> 11 O one will focus.

Ian C. Mortimer: So, at some point, we will be leveraging partners to access jurisdictions outside of the US. Obviously, we don't guide on that timing. But that is something that, as we think about the long-term development and market access of the drugs in Xeon 1101, we'll focus ourselves in the US, and then we would, at the appropriate time, engage with partners outside the US. Thank you. Your next question comes from the line of Joseph Tome with T.D. Cowan.

Speaker Change: Ourselves in the U S. And then we would at the appropriate time engage with partners ex U S.

Speaker Change: Thank you.

Speaker Change: Yeah.

Speaker Change: Your next question comes from the line of Joseph Thome with TD Cowen Your line is open.

Joseph John: Hi, there good afternoon, and thank you for taking my questions. Maybe just one on the three phase III studies for major depressive disorder. I guess are these going to be just three replicate trials or.

Joseph John: In terms of the patient population enrolled or will you potentially use one of them to examine like an antidepressant unresponsive population or <unk>, how should we think about that and then second just on the Ham D measure itself. I guess is there something mechanistically about 11 O. One that makes the benefit clear on the Ham D scale versus the Madras or.

Operator: Your line is open. Hi there, good afternoon, and thank you for taking my questions. Maybe just one of the three phase three studies for major depressive disorder. I guess, are these gonna be just three replicate trials or in terms of patient population enrolled, or will you potentially use one of them to examine like an antidepressant unresponsive population or TRD? How should we think about that? And then second, just on the HAM-D measure itself, I guess. Is there something mechanistically about 1101 that makes the benefit clear on the HAM-D scale versus the Madras, or was it really just what you saw on phase two and maybe some of that decreased variability in the response that made you go forward with that measure? Thanks. Thanks, Joe.

Joseph John: Was it really just what you saw in the phase two and maybe some of that decrease variability.

Joseph John: And the response that made you go forward with that measure.

Speaker Change: Thanks, Joe.

Speaker Change: Chris are you good.

Speaker Change: Through the three phase III studies in our thinking about the population there and then also.

Speaker Change: A question around <unk> 17, yes.

Chris: Yeah sure, let's start with Ham D 17.

Chris: I think it's sort of already alluded to the point that I think is the major advantage for him <unk> 17 over.

Christopher John Kenney: Chris, are you good to go through the three phase three studies and think about the population there and then also the question around HEMD 17? Yeah, sure. Let's start with HAM-D17. I think I sort of already alluded to the point that I think is the major advantage for HAM-D17 over Amadris, which is really the variability, not just in our study, but in other studies. And it's not subtle.

Chris: Our module, which is really the variability and not just in our study but in other studies and it's it's not subtle it's really quite striking so I think that's the major factor for why it's beneficial as far as the other the three studies that we're going to do in major depressive disorder, we're considering them to be very similar to one another.

Chris: One active arm versus placebo similar size and the big difference from one study to the next will largely be considering different jurisdictions to to.

Christopher John Kenney: It's really quite striking, so I think that's the major factor for why it's beneficial. As far as the other three studies that we're going to do in major depressive disorder, we consider them to be very similar to one another. One active arm versus placebo, similar size.

Chris: To be able to make sure that you can operationally execute and pull off the studies within a reasonable period of time, but for the most part we're looking at them is pretty.

Chris: Pretty much identical and the purpose of that third study is to mitigate risk.

Chris: Largely similar to what we've done with focal onset seizures, we've completed ex tool and we've got extra will to a next 12 three running similar similar approach to M. D. D N focal onset seizures.

Christopher John Kenney: And the big difference from one study to the next will largely be considering different jurisdictions to be able to make sure that you can operationally execute and pull off the studies within a reasonable period of time. But for the most part, we're looking at them as pretty much identical, and the purpose of that third study is to mitigate risk. Largely, similar to what we've done with focal onset seizures, we've completed XTOL, and we've got XTOL-2 and XTOL-3 running. A similar approach to MDD and focal. Great. Thanks, Chris.

Great: Great. Thank you Chris.

Speaker Change: And Joe maybe I can just add just to answer your very specific question, Chris I think it was embedded in his answer that the that our current thinking is that the three studies would look very much the same which means the patient population would be to say we wouldn't be looking as you as you asked about.

Speaker Change: Like a TRT population and one of those studies, we would think about it really in the moderate to severe <unk> population, but not the TRT population.

Christopher John Kenney: And Joe, maybe I can just add, just to answer your very specific question, Chris, I think kind of it was embedded in his answer that our current thinking is that the three studies would look very much the same, which means the patient population would be the same. We wouldn't be looking as you asked about, like, a TRD population in one of those studies. We would really think about it in the moderate to severe MDD population but not the TRD population. Perfect. Thank you. Yeah Your next question comes from the line of Brian Scorney with Baird. Your line is open. Hey, good afternoon, everyone.

Speaker Change: Perfect. Thank you.

Speaker Change: Yes.

Speaker Change: Your next question comes from the line of Brian <unk> with Baird. Your line is open.

Brian Abrahams: Hey, good afternoon, everyone. Thanks for taking my question.

Brian Abrahams: Also on the on the <unk> 0.1, 0.7 program Neurocrine, given given what seems to be somewhat disparate results from a one eight inhibitor. There's been some questions that we've gotten about differential expression.

Brian Abrahams: In different tissues of not just sort of a clinical design issue here. So I guess, how do you think about expression of now $1 seven how does this inform sort of what piece of the indications. You think are sort of are most likely to be pursued for this target I think $1 seven.

Operator: Thanks for taking my question. Also, on the NAF 1.7 program, given what seems to be somewhat disparate results from the 1.8 inhibitor, there's been some questions that we've gotten about differential expression in different tissues. It's not just sort of a clinical design issue here. So, I guess, how do you think about NAF 1.7 expression?

Brian Abrahams: And fully expressed in DRG neurons. So just as you kind of like going forward, what do you imagine for.

Brian Abrahams: For the path for clinical development here.

Speaker Change: Yes, I think it's a really good question, Brian is just very probably premature to go too far down that path, but I do want to.

Speaker Change: Kind of pull on the thread of Hugh.

Ian C. Mortimer: And how does this inform sort of what key indications you think are sort of the most likely to be pursued for this target? I think 1.7 is preferentially expressed in DRG neurons. So, just as you kind of like, go forward, what do you imagine the path for clinical? Yeah, I think it's a really good question, Brian.

Speaker Change: That you've made in your statement, which is I think expression matters and so the distribution and the properties pharmaceutical properties of the chemistry is matter and I was kind of alluding to this a little bit in one of the earlier questions is I think thats a lot of what we've learned asset xenon.

Speaker Change: It has been in the field for a number of years is that I do think we need appropriate molecules that are going to access that target preferably, but as you say there is central expression as well in terms of really designing out.

Ian C. Mortimer: It's probably very probably premature to go too far down that path, but I do want to, you know, kind of pull on the thread that you've made in your statement, which is that I think expression matters. And so the distribution and the properties, pharmaceutical properties of the chemistries matter. And I was kind of alluding to this a little bit in one of the earlier questions, I think that's a lot of what we've learned at Xenon, as being in the field for a number of years, is that I do think we need appropriate molecules that are going to access the target peripherally. But as you say, there is central expression as well in terms of really designing out.

Speaker Change: And so we believe we have chemistries that are going to.

Speaker Change: Appropriately.

Speaker Change: Dress.

Speaker Change: We're now 1.7 is expressed and as a reminder, we there are these patients out there that are these homozygous loss of function, where they have none of the protein and they don't feel pain, regardless of noxious Emil.

Speaker Change: We don't think you need that kind of receptor occupancy some of the genetics actually teaches us in the literature that we don't need that kind of receptor occupancy, but I think we're expression is in the properties of the drug is absolutely going to matter.

Ian C. Mortimer: And so we believe we have chemistries that are going to appropriately address where we are now 1.7 is expressed. And as a reminder, there are these patients out there that have this homozygous loss of function where they have none of the protein, and they don't feel pain regardless of noxious stimuli. We don't think you need that kind of receptor occupancy. Some of the genetics actually teaches us in the literature that we don't need that kind of receptor occupancy.

Speaker Change: So we think too far at around does that give us a better indication of where we should go in terms of the ultimate.

Speaker Change: <unk> therapeutic utility in our broader narrow I think it's just too premature we're really focused on getting through IND.

Speaker Change: IND, enabling studies and then doing some of that early human proof of concept work and then I think we can kind of broaden out a little bit more and think about the development plan from there.

Speaker Change: Your next question comes from the line of Marc Goodman with Leerink Partners. Your line is open.

Ian C. Mortimer: But I think where expression is, and the properties of the drug, are absolutely going to matter as we think too far ahead. Does that give us a better indication of where we should go in terms of the ultimate therapeutic utility and how broad or narrow? I think it's just too premature.

Marc Harold Goodman: As you know I was curious as you've.

Marc Harold Goodman: Dove into the data from M D D a little bit more on the safety profile and just why do you think the safety profile was just different in that population relative to the epilepsy population and then Sherry maybe you could just give us a sense of R&D spend for this year. Thank you.

Ian C. Mortimer: We're really focused on getting through enabling studies and then doing some of that early human proof of concept work. And then I think we can kind of broaden out a little bit more and think about the development plan from there. Your next question comes from the line of Mark Goodman with Lerink Partners. Your line is open.

Mark: Mark Yes.

Mark: I'll kind of open up with a quick comment, but I'll pass it to Chris Kenny to kind of give his perspective.

Christopher John Kenney: But yes, I would actually say that was surprising to us when we unblinded ex Nova.

Christopher John Kenney: The Tolerability profile and I know, we had a lot of questions.

Operator: Ian, I was curious as you've dived into the data from MDD, a little bit more on the safety profile and just why do you think the safety profile was just different in that population relative to the epilepsy population? And then, Sherry, maybe you could just give us a sense of R&D spend for this year. Thank you. Thank you. Thank you.

West with investors and with analysts on.

Christopher John Kenney: You know what is the tolerability profile going to be like in an MD population.

Christopher John Kenney: As we compare that to the epilepsy population and.

Christopher John Kenney: And we were pleasantly surprised when we unblinded data that OSI Tolerability, we probably again with the caveat of a cross trial comparison it looks like we have.

Christopher John Kenney: Mark, yeah, I'll kind of open up with a quick comment, but I'll pass it to Chris Kenney to kind of give his perspective. But yeah, I would actually say that was surprising to us when we unblinded Exnova, that the tolerability profile, and I know we had a lot of questions with investors and with analysts about, you know, what is the tolerability profile gonna be like in an MDD population as we compare that to the epilepsy population? And we were pleasantly surprised when we unblinded the data and found that it looks like tolerability. Again, with the caveat of a cross- trial comparison, it looks like we have a better tolerability profile in depression. Chris, maybe you can give your perspective on the reasons.

Christopher John Kenney: A better Tolerability profile and depression, Chris maybe you can give your perspective on on on the reasons.

Chris: And I know, we may not be able to answer it perfectly but at least some of our thinking internally on Hawaii.

Chris: Yeah, I mean, you know going into it I mean, we weren't really sure what to expect and so it was it was a pleasant surprise to see the tolerability of the way it was.

Two reasons I can come up with worldwide it might be tolerated better in the <unk> population and the focal onset seizures.

Chris: One is that the concomitant medications remember that <unk> was done as a mono therapy, whereas the X Tole study was completed as adjunct to other anti seizure medications and they were pretty.

Chris: Pretty significant disease that X tole population half of them were taking three anti seizure medications and about 40% or so we're taking two so they were taking more concomitant medications I think that's probably the best answer to your question. If you want to get a little more academic.

Christopher John Kenney: And I know we may not be able to answer it perfectly, but at least some of our thinking internally on the why. Yeah, I mean, going into it, we weren't really sure what to expect. And so it was, it was a pleasant surprise to see the tolerance the way it was.

Chris: There is evidence in non clinical experiments that kv seven is down regulated.

Chris: Depression models, and so I don't know if thats the case in patients with depression.

Chris: I don't think we're ever going to be able to know for sure, but if there were a down regulation.

Christopher John Kenney: Two reasons I can come up with why it might be tolerated better in the MDD population than in the focal onset seizures. One is that, you know, the concomitant medications. Remember, the Ex Novo study was done as monotherapy, whereas the XTOL study was completed as adjunct to other anti-seizure medications. And they were pretty, you know; they had pretty significant diseases that that XTOL population, half of them were taking three anti-seizure medications, and about 40% or so were taking two. So they were taking more concomitant medications. I think that's probably the best answer to your question. If you want to get a little more academic, you know, there is evidence in non-clinical experiments that KB7 is downregulated in depression models.

Chris: <unk> of <unk>, seven and Youre coming in with a KD seven opener you might expect those patients to tolerate the drug better.

Chris: One thing you know not to spend too much time on this but eventually we will have safety data in the exact trial with PGE Tcs they tend to be on less or.

Chris: Fewer concomitant anti seizure medications and so we'll be able to compare the 25 milligram dose in that population to force and see if theres any difference there it may get to the bottom of your question.

Speaker Change: And Mark just to address your point on R&D spend in 2024.

Speaker Change: So as you think about that the epilepsy program.

Speaker Change: As Ian mentioned earlier this program each of the studies is about 80 to 100 sites and we're going to multiple jurisdictions. So as we think about over 2024 now we've got our sites fully up and running and we're going to complete.

Christopher John Kenney: And so I don't know if that's the case in patients with depression. I don't think we're ever going to be able to know for sure, but if there was a downregulation of KB7 and you're coming in with a KB7 opener, you might expect those patients to tolerate the drug better. I mean, I think one thing, you know, not to spend too much time on this, but eventually, we'll have safety data in the exact trial with PGTCS. They tend to be on less, and there are fewer concomitant anti-seizure medications.

Enrollment.

Speaker Change: In late 'twenty early 'twenty five.

Speaker Change: We are going to see an incremental increase as we look at the cost across the epilepsy program.

Speaker Change: M D D.

Speaker Change: Sure we've guided that we're going to have their FDA interaction in April.

Speaker Change: And we're going to start our first study in the second half of the year. So we're not going to see a significant increase as it relates to the clinical development costs, yet for <unk> and 'twenty four we will see that really pick up more than 25 and.

Christopher John Kenney: And so we'll be able to compare the 25 milligram dose in that population to FOS and see if there's any difference there. It may get to the bottom of your question. And Mark, just to address your point on R&D spend in 2024, so as we think about the epilepsy program, as Ian mentioned earlier, this program, each of the studies is about 80 to 100 sites, and we're going to multiple jurisdictions. So, as we think about 2024, now we've got our sites fully up and running, and we're going to complete enrollment in late 2024, early 2025. So, we are going to see an incremental increase as we look at the costs across the epilepsy program. For MDD, we've guided that we're going to have an SEA interaction in April, and we're going to start our first study in the second half of the year. So, we're not going to see a significant increase as it relates to clinical development costs for MDD in 2024. But we'll see that really pick up more in 2025.

Speaker Change: And then on the preclinical programs.

Speaker Change: As we discussed moving multiple product candidates into IND, enabling studies, so we will see an incremental step up as well.

Speaker Change: Overall, I think we don't we don't guide and get specific.

Speaker Change: Numbers, but directionally, we will see a step up increase in 24 over what we saw in 'twenty three.

Speaker Change: Thanks.

Speaker Change: Your next question comes from the line of Mohit Bansal with Wells Fargo. Your line is open.

Speaker Change: Okay.

Speaker Change: This is Adam on for Mohit. Thanks for taking the question with enough cash runway to support phase three development in epilepsy and M. D. D would you be able to compare how MPD development would compare to epilepsy in terms of power requirements and costs and also what data from the epilepsy program you can leverage for the MDT setting. Thanks.

Speaker Change: Thanks, Adam.

Speaker Change: I'm happy to take the second one and then Sherry do you want to provide some perspective just on.

Sherry Aulin: And then on the preclinical programs, we are, as we discussed, moving multiple product candidates into I&D enabling studies. So, we'll see an incremental step up as well. So overall, I think, you know, we don't we don't guide and give specific numbers, but directionally, we'll see a step-up increase in 24 over what we saw in 23. Your next question comes from the line of Mohit Bansal with Wells Fargo. Your line is open. This is Adam An from OHIT.

Speaker Change: Kind of sizing in costs overall for <unk> versus <unk>.

Speaker Change: So in terms of that we didn't go into this earlier, but at our end of phase II meeting one of the questions that we will be discussing.

Sherry Aulin: With FDA is just the size of the safety database. So Chris had mentioned, we learned a huge amount with our FDA interaction and with the Neurology Division post tax tall. So we had a lot of questions around so we have a lot of comfort around the clinical pharmacology package the non clinical package. The overall safety database.

Operator: Thanks for taking the question. With enough cash runway to support phase 3 development in epilepsy and MDD, would you be able to compare how MDD development would compare to epilepsy in terms of trial requirements and costs? And also, what data from the epilepsy program you can leverage for the MDD setting? Thanks. Adam

Sherry Aulin: That's going to be required in epilepsy, one of the questions.

Sherry Aulin: That will discuss with FDA in April of this year in psychiatry is how much of that epilepsy safety safety database can we leverage.

Sherry Aulin: To an application or a dossier and depressions so.

Speaker Change: So we'll be able to get back to you on that.

Ian C. Mortimer: I'm happy to take the second one, and then Sherry, do you want to provide some perspective just on the kind of sizing and costs overall for MDD versus epilepsy? So, in terms of that, we didn't go into this earlier, but at our end of phase 2 meeting, one of the questions that we will be discussing with FDA is just the size of the safety database. So, Chris mentioned, we learned a huge amount with our FDA interaction with the neurology division post-X toll. So we had a lot of questions around.

Speaker Change: As we've had those FDA interactions on what those requirements are I mean, the benefit that we have with axion 11 O. One right now is and Chris mentioned this in his prepared remarks is we have a huge amount of safety data in a real.

Speaker Change: Significant knowledge about the profile of the drug we now have over 600 patient years of exposure, we have long term dosing more than four years, we will have patients that'll go out more than five years. This year. So I think we can leverage a huge amount of what we know about the molecule.

Sherry Aulin: So we have a lot of comfort around the clinical pharmacology package, the non-clinical package, the overall safety database that's going to be required in epilepsy. One of the questions that we'll discuss with FDA in April of this year in psychiatry is how much of that epilepsy safety database can we leverage into an application or a dossier in depression. So, we'll, we'll be able to get back to you on that as we've had those FDA interactions and what those requirements are. I mean, the benefit that we have with Xeon 1101 right now, and Chris mentioned this in his prepared remarks, is that we have a huge amount of safety data and real significant knowledge about the profile of the drug. You know, we now have over 600 patient years of exposure. We have been doing long-term dosing for more than 4 years.

Speaker Change: And I think we will get credit for that.

Speaker Change: And depression and the question is what else is FDA going to require specifically in the labeled population so standby for that sure.

Speaker Change: On the costing side.

Speaker Change: Yeah I was also going to add there's a lot we can hopefully elaborates on the safety database piece that a lot of the work that we're doing in development for epilepsy can also be leveraged for depression. So let me think broader and the clinical.

Speaker Change: Fannie themselves the <unk> Pharm package and.

Speaker Change: The non clinical toxicology studies that we run a lot of the work that we do on the CMC side with respect.

Speaker Change: Develop development.

Speaker Change: Registration and validation batches and things of that sort can also be leveraged in the depression.

Ian C. Mortimer: We'll have patients that will go out more than 5 years this year. So, I think we can leverage a huge amount of what we know about the molecule, and I think we'll get credit for that in depression. The question is, what else is FDA going to require specifically in the labeled population? So stand by for that Sherry on the cost insight.

Speaker Change: Graham and so when we look at the totality of the cost and you were running a broad Andy D program with three studies.

Studies are going to be probably larger than the epilepsy studies that we're running.

Speaker Change: And I would say roughly as we think about the amount of capital that we've raised which was 345 million at the end of last year.

Sherry Aulin: Yeah, I was also going to add, you know, there's a lot we can hopefully leverage on the safety database piece, but a lot of the work that we're doing in development for epilepsy can also be leveraged for depression. So, as we think broader than the clinical studies themselves, the ClinPharm package, the non-clinical toxicology studies that we run, a lot of the work that we do on the CMC side with respect to development, registration, and validation batches and things of that sort can also be leveraged in the depression program. And so, when we look at the totality of the cost, I mean, we're running a broad NDD program with three studies. The studies are probably going to be larger than the epilepsy studies that we're running. And I would say roughly so, as we think about the amount of capital that we've raised, which was 345 million at the end of last year.

That has given us the ability to fully fund the depression program. In addition to extending our cash runway by by year end.

Speaker Change: So generally speaking.

Speaker Change: It's faster than I would say generally cheaper to run the depression program as we compare that to epilepsy and in particular, when you think about epilepsy and one of the big cost is X.

Speaker Change: <unk> open label.

Speaker Change: Work that we're doing so.

Speaker Change: For example, and I was told we had an open label and that now is entering its first year and then we recently said that we've extended that to from five to seven years. So that is a significant cost, which we don't expect well that will be the case for depression.

Sherry Aulin: That's given us the ability to fully fund the depression program in addition to extending our cash runway by a year. And so, generally speaking, you know, it's faster and, I would say, generally cheaper to run the depression program as we compare that to epilepsy. And in particular, if you think about epilepsy, one of the big costs is the extended open-label work that we're doing. So, you know, for example, in XTOL, we had an open-label trial that is now entering its fifth year.

Speaker Change: Okay.

Speaker Change: Due to time constraints. Our last question comes from the line of Laura Chico with Wedbush Securities. Your line is open.

Laura Kathryn Chico: Thanks, very much for fitting me in just two quick ones and following up on that I apology apologies, if I missed part of it but could there be a scenario in which you just due to depression studies I guess given the large database.

Laura Kathryn Chico: Leverage at the epilepsy dataset I'm, just trying to understand could there be a scenario, where you don't necessarily need to do three trials and would that be a discussion point and the end of phase two meeting and then related to depression. It looks like the timing for the Mount Sinai Depression study has been extended based on that Glenn trial public thing.

Sherry Aulin: And we recently said that we've extended that to from five to seven years. So that is a significant cost, which we don't expect will be the case for depression. Due to time constraints, your last question comes from the line of Laura Chico with Wedbush Security. Your line is open. Thanks very much for fitting me in.

Laura Kathryn Chico: I understand this is not a gating item at this point for the trial initiation or FDA discussions, but I guess I'm curious how much relevance. This study actually carry at this point to you and what is your working assumption in terms of data readout. Thank you.

Operator: Just two quick ones and follow up on that. I apologize if I missed part of it, but could there be a scenario in which you just do two depression studies? I guess, given the large database and the leverage of the epilepsy dataset, I'm just trying to understand, could there be a scenario where you don't necessarily need to do three trials? And would that be a discussion point at the end of the Phase 2 meeting? And then related to depression, it looks like the timing for the Mount Sinai depression study has been extended based on the ClinTrial posting. And I understand this is not a gating item at this point for the trial initiation or FDA discussions, but I guess I'm curious, how much relevance does this study actually carry at this point for you? And what's your working assumption in terms of data readout? Thank you. Thanks, Laura.

Speaker Change: Thanks, Laura.

Speaker Change: Yeah, I don't when we think about the two versus three depression studies.

Speaker Change: I don't think thats going to be an FDA.

Speaker Change: Question.

Speaker Change: Meaning as you suggested if we had to excuse me. If we had two positive studies that that would meet the requirements for filing and as you suggested and we've highlighted we're going to have a huge amount of safety data around the molecule. So when we think about the decision of running two studies versus <unk> III studies in depression.

Speaker Change: It's really more around risk mitigation.

Speaker Change: And just some of the variability that you see in depression studies, rather than specifically that we believe that's either going to be a regulatory requirement or required for a certain amount of safety data. So I hope that helps to just clarify kind of our thinking around three versus two.

Ian C. Mortimer: Yeah, I don't, when we think about the two versus three depression studies, I don't think that's going to be an FDA question, meaning, as you've suggested, if we had two, excuse me, if we had two positive studies, that would meet the requirements for filing, and as you suggested, and we've highlighted, we're going to have a huge amount of safety data around the molecule. So when we think about the decision of running two studies versus three studies in depression, it's really more around risk mitigation and just some of the variability that you see in depression studies rather than specifically that we believe that's either going to be a regulatory requirement or required for a certain amount of safety data. So I hope that that helps to just clarify our thinking around three versus two. And then on the IST, yeah, we don't have a lot of control over the IST.

Speaker Change: And then.

Speaker Change: On the ISP, yes, we don't have a lot of control over.

Speaker Change: Over the ISG. Obviously this is at two centers at Mount Sinai and Baylor.

Speaker Change: Academic around study, we provide drug supply and obviously there is a collaboration and coordination between our institutions by it but we don't really have an influence in terms of enrollment.

Speaker Change: As we've talked about not gating to our plans moving forward and out where we're not waiting for those data.

Speaker Change: And we really are guided by.

Speaker Change: Dr MRO and Dr. Matthew in terms of how they're doing and when potentially the data would be available. So when we have a better idea of when that top line data would be available that we're happy to share it with you at that time.

Ian C. Mortimer: Obviously, this is at two centers at Mount Sinai and Baylor. It's an academically run study. We provide the drug supply, and obviously, there is collaboration and coordination between our institutions, but we don't really have influence in terms of enrollment as we've talked about not gating to our plans moving forward. And we're not waiting for the data, and we really are guided by Dr. Murrow and Dr. Matthew in terms of how they're doing and when, potentially, the data would be available. So when we have a better idea of when that top line data will be available, we'll be happy to share it with you at that time.

Speaker Change: Thank you.

Thank you for your participation. This concludes today's call you may now disconnect.

Speaker Change: [music].

Operator: Thank you. Thank you for your participation. This concludes today's call. You may now disconnect.