Q2 2024 Xenon Pharmaceuticals Inc Earnings Call

Meg: Thank you for standing by. My name is Meg, and I will be your conference operator today. At this time, I would like to welcome everyone to the Q2 2024 Xenon Pharmaceuticals, Inc. earnings conference call.

Operator: At this time, I would like to welcome everyone to the Xenon Pharmaceuticals Inc. Earnings Conference Call. 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 this time, simply press star followed by the number 1 on your telephone keypad. If you would like to rephrase your question, press star 1 again. Thank you. I would now like to turn the conference over to Mr. Shad Khojaret, VP IR for Xenon. Please go ahead.

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

Meg: After the speaker's remarks, there will be a question and answer session.

Meg: If you would like to ask a question during this time, simply press star followed by the number 1 on your telephone keypad. If you would like to redraw your question, press star 1 again.

Meg: Thank you. I would now like to turn the conference over to Mr. Chad Fugere, VP, IR for Xenon. Please go ahead.

Shad Khojaret: Good afternoon, Thank you for joining us on our call and webcast to discuss Xenon's second quarter 2024 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 Sherry Aulin, Xenon's Chief Financial Officer, along with Dr. Chris von Seggern, Xenon's Chief Commercial Officer, who will be available during the Q&A period. And we'll begin with a summary of our recent progress across our business, including a summary of our expanding preclinical pipeline programs.

Chad Fugere: Good afternoon. Thank you for joining us on our call and webcast to discuss Xenon's second quarter 2024 financial and operating results.

Speaker Change: Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer, Dr. Chris Kenney, Xenon's Chief Medical Officer, and Sherry Aulin, Xenon's Chief Financial Officer, along with Dr. Chris von Seggern, Xenon's Chief Commercial Officer, who will be available during the Q&A period.

Speaker Change: And we'll begin with a summary of our recent progress across our business.

Shad Khojaret: Chris Kenney will provide an overview of our ongoing clinical stage programs, including our plans for major depressive disorder, or MDD, and Sherry will close with a summary of our financial results and anticipated milestones. We will then open the call to your questions. Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the timing of and potential results from clinical trials, the potential efficacy, safety profile, future development plans, and current and anticipated indications, address full market, regulatory success, and commercial potential of our and our partners' product candidates.

Speaker Change: Chris Kenney will provide an overview of our ongoing clinical stage programs, including our plans and major depressive disorder, or MDD. And Sherry will close with a summary of our financial results and anticipated milestones.

Speaker Change: We will then open the call up for your questions.

Speaker Change: Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the timing of and potential results from clinical trials, the potential efficacy, safety profile, future development plans, and current and anticipated indications

Speaker Change: Address the market, regulatory success, and commercial potential of our and our partners' product candidates.

Speaker Change: The efficacy of a clinical trial design.

Speaker Change: Our ability to successfully develop and achieve milestones in our clinical development programs.

Speaker Change: The timing and results of our interactions with regulators, our ability to successfully develop and obtain regulatory approvals, anticipated timing of the top-line data readout for our clinical trials of Adhesive Calendar, and our expectation that we will have sufficient cash to fund operations into 2027.

Shad Khojaret: Our ability to successfully develop and achieve milestones in our clinical development program; the timing and results of our interactions with regulators, our ability to successfully develop and obtain regulatory approvals, anticipated timing of the top-line data readout for our clinical trials of adhesive counter, and our expectation that we will have sufficient cash to fund operations into 2027. Today's press release summarizing Xenon's second quarter 2024 financial results and the accompanying quarterly report on Form 10-Q will be made available under the investor section of our website at xenon-pharma.com and filed with the SEC and on CDER Plus. Now, I would like to turn the call over to Ian.

Speaker Change: Today's press release summarizing Xenon's second quarter 2024 financial results and the accompanying quarterly report on Form 10-2 will be made available under the investor section of our website at xenon-pharma.com and filed with the FCC and on CDER Plus.

Speaker Change: Now I would like to turn the call over to Ian.

Ian Mortimer: Thank you, Chad, and good afternoon, everyone, and thank you for joining us on our call today. This is an exciting time for Xenon as we expand our pipeline and further progress towards becoming a fully integrated biopharmaceutical company. We remain sharply focused on three key areas across the business where we have continued to make significant advancements this past quarter. Number one, the continued execution across our phase three program is that to counter epilepsy studies.

Ian: Thank you, Chad, and good afternoon, everyone, and thank you for joining us on our call today. This is an exciting time for Xenon as we expand our pipeline and further progress towards becoming a fully integrated biopharmaceutical company.

Ian: We remain sharply focused on three key areas across the business where we have continued to make significant advancements this past quarter.

Ian: Number one, the continued execution across our phase three is that to counter epilepsy studies.

Ian Mortimer: Number two, preparation for our Z2Calendar MDD program, with a focus on finalizing our phase three protocol and study initiation later this year, and number three, the advancement of our portfolio of next-generation ion channel modulators. For the last decade, epilepsy research has been a primary focus at CNS.

Ian: Number two, preparation for our Z2 Calendar MDD program, with a focus on finalizing our Phase 3 protocol and study initiation later this year. And number three, the advancement of our portfolio of next-generation ion channel modulators.

Ian: Over the last decade, epilepsy research has been a primary focus at Xenon, driven by a continued and significant unmet medical need, with many patients still struggling to control focal onset seizures and primary generalized tonic-clonic seizures despite available medications.

Ian Mortimer: Driven by a continued and significant unmet medical need, with many patients still struggling to control focal onset seizures and primary generalized tonic-clonic seizures despite available medication, the continued progress of the Zatu Calendar in our broad Phase 3 epilepsy program remains core to our business. As a reminder, AZETU-CalNER is the only KV7 potassium channel opener in development with Phase IIb efficacy and long-term safety data in epilepsy patients. No other KV7 molecules in development have efficacy and safety data in epilepsy or depression.

Ian: For that reason, the continued progress of the Zatu Calendar in our broad Phase III Epilepsy Program remains core to our business.

Ian: As a reminder, AZETU-CalNER is the only KV7 potassium channel opener in development with Phase IIb efficacy and long-term safety data in epilepsy patients.

Ian: No other KV7 molecules in development have efficacy and safety data in epilepsy or depression patients.

Ian Mortimer: And we have set an incredibly high bar for other KV drugs in development to achieve the impressive attributes of a Zatu calendar. Data from our Phase 2b X-Toll Epilepsy trial demonstrated the best placebo-adjusted clinical efficacy in the most refractory patient population ever trialed, as well as a favorable tolerability profile in adult patients with focal onset seizures. Furthermore, long-term efficacy data generated through our XTOL Open Label Extension support increased seizure reduction, with patients out to 30 months on a ZETU calendar showing a greater than 90% reduction in median monthly seizure frequency, while approximately one in four patients on a ZETU calendar for at least two years have been seizure-free for a full year or longer.

Ian: and we have set an incredibly high bar for other KV drugs in development to achieve the impressive attributes of a Zetucaliner.

Ian: Data from our Phase 2b X-Hole Epilepsy trial demonstrated the best placebo-adjusted clinical efficacy in the most refractory patient population ever trialed, as well as a favorable tolerability profile in adult patients with focal onset seizures.

Ian: Furthermore, long-term efficacy data generated through our XTOL open-label extension support increased seizure reduction, with patients out to 30 months on a ZETU calendar showing a greater than 90% reduction in median monthly seizure frequency.

Ian: While approximately one in four patients on a ZETU calendar for at least two years have been seizure-free for a full year or longer

Ian Mortimer: In addition, we now have over 600 patient years of exposure, as well as patients on azethucaloner for more than four years in the OLE, giving us and the epilepsy community tremendous confidence around the future potential of azethucaloner to address the need for new anti-seizure medication. With that in mind, we continue to progress patient enrollment across our ongoing phase three epilepsy studies, with top-line results from XTOL2 in focal onset seizures anticipated in the second half of 2025. Negative results would enable the submission of our MDA with the goal of advancing the Zatu calendar towards commercialization.

Ian: In addition, we now have over 600 patient years of exposure, as well as patients on azethucalonar for more than four years in the OLE, giving us and the epilepsy community tremendous confidence around the future potential of azethucalonar to address the need for new anti-seizure medications.

Ian: With that in mind, we continue to progress patient enrollment across our ongoing Phase 3 epilepsy studies, with top-line results from XTOL2 in focal onset seizures anticipated in the second half of 2025.

Ian: Positive results would enable the submission of our NDA with the goal of advancing a Zatu Calendar towards commercialization.

Ian Mortimer: Overall, we are very pleased with the progress in our Phase 3 program, and it is exciting to be in a position to develop what we believe will be the next important medicine to treat patients with focal epilepsy. Focusing now on our IZETU Calendar MDD program, we recently presented the Phase II Ex Nova trial results at the American Society of Clinical Psychopharmacology, or ASCP, the annual meeting held in Miami in May. This medical meeting was a great opportunity for us to continue to raise awareness of data supporting IZETU Calendar's potential differentiated profile versus standard of care agents and MDD, including a rapid onset of effects, tolerable safety profile, and a potential benefit on anhedonia, a common comorbidity with a significant unmet need. These data form the basis of our decision to advance the ZETU calendar into a Phase III program in MDD, which we expect to initiate in the second half of this year.

Ian: Overall, we are very pleased with the progress in our Phase 3 program, and it is exciting to be in a position to develop what we believe will be the next important medicine to treat patients with focal epilepsy.

Ian: Focusing now on our ZETU Calendar MDD program, we recently presented the Phase II Ex Nova trial results at the American Society of Clinical Psychopharmacology, or ASCP, the annual meeting held in Miami in May.

Ian: This medical meeting was a great opportunity for us to continue to raise awareness of data supporting Izzetio Kaliner's potential differentiated profile versus standard of care agents and MDD.

Ian: including a rapid onset of effect, tolerable safety profile, and a potential benefit on anhedonia, a common comorbidity with a significant unmet need.

Ian: These data form the basis of our decision to advance the ZETU calendar into a Phase 3 program in MDD, which we expect to initiate in the second half of this year.

Ian Mortimer: We are also continuing to evaluate additional clinical development opportunities for ZETU-COM, focusing specifically on other neuropsychiatric indications where a scientific rationale exists, as well as a commercial fit with epilepsy and MDT. Beyond the ZETU calendar, we continue to expand Xenon's leadership in the small molecule ion channel field, based on our extensive work in channelopathies over the past two decades as we built out a world-class discovery team. We have recently expanded our pipeline by nominating multiple development track candidates, or DTCs, targeting potassium and sodium.

Ian: We are also continuing to evaluate additional clinical development opportunities for Zettu-Kallner, focusing specifically on other neuropsychiatric indications where a scientific rationale exists, as well as a commercial fit with epilepsy and MDD.

Ian: Beyond the ZETU calendar, we continue to expand Xenon's leadership in the small-molecule ion channel space.

Ian: Based on our extensive work in channel offices over the past two decades, as we built out a world-class discovery chain.

Ian: We have recently expanded our pipeline by nominating multiple development track candidates, or DTCs, targeting potassium and sodium channels.

Ian Mortimer: Achieving DTC status is a critical milestone for our program, as it reflects a molecule that has met our rigorous criteria to be advanced into GLP toxicology studies, and if successful, will form the basis of an IND or IND-equivalent. One of our key areas of focus are potassium channels, as we believe KV7 offers potential pipeline-in-a-mechanism opportunities. The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional KV7 product candidates that are chemically diverse from a Z2 calendar and can provide additional development opportunities across a broad range of therapeutic indications, including seizure disorders, pain, and neuropsychiatric conditions.

Ian: Achieving DTC status is a critical milestone for our program, as it reflects a molecule that has met our rigorous criteria to be advanced into GLP toxicology studies, and if successful, will form the basis of an IND or IND-equivalent submission.

Ian: One of our key areas of focus are potassium channels, as we believe KV7 offers potential pipeline in a mechanism opportunities.

Ian: The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional KV7 product candidates that are chemically diverse from a ZETU calendar and can provide additional development opportunities across a broad range of therapeutic indications.

Ian: including seizure disorders, pain, and neuropsychiatric conditions.

Ian Mortimer: For that reason, we continue to advance multiple KV7 molecules so that we can potentially extend the reach of this promising and differentiated mechanism to more patients. Building on our extensive experience against the KV7 target developed over many years, we have made significant progress across several promising novel chemical series, and this past quarter, we nominated multiple KV7 development track candidates, with a lead candidate now in IND enabling studies, to support our goal of filing an IND or IND equivalent in 2025.

Ian: For that reason, we continue to advance multiple KV-7 molecules so that we can potentially extend the reach of this promising and differentiated mechanism to more patients in need.

Ian: Building on our extensive experience against the KV7 target developed over many years, we have made significant progress across several promising novel chemical series, and this past quarter, we nominated multiple KV7 development track candidates.

Ian: with a lead candidate now in IND Enabling Studies.

Ian: to support our goal of filing an IND or IND equivalent in 2025.

Ian Mortimer: We believe these advancements in our KV7 preclinical program, combined with the promising and robust clinical data we have generated to date with azethutaliner in epilepsy and MDD, set Xenon at the forefront of both drug discovery and development for this important mechanism. Turning now to our sodium channel work. As an early pioneer in the space, xenon scientists focused on identifying genetic targets associated with rare phenotypes. Through this early work, it was uncovered that individuals with complete loss-of-function mutations in the gene encoding for NAV1.7 have an inability to perceive pain, while those individuals with gain-of-function mutations have non-precipitative spontaneous severe pain, leading to the identification of NAV1.7 as an important pain While other sodium channels involved in the transmission of pain signals, such as NAV1.8, have recently been clinically validated, we believe NAV1.7 has by far the strongest genetic validation.

Ian: We believe these advancements in our KV7 preclinical program, combined with the promising and robust clinical data we have generated to date with azethucalin in epilepsy and MDD, set xenon at that forefront of both drug discovery and development for this important mechanism.

Ian: Turning now to our sodium channel work. As an early pioneer in the space, xenon scientists focus on identifying genetic targets associated with rare phenotypes.

Ian: Through this early work, it was uncovered that individuals with complete loss-of-function mutations in the gene encoding for NAV1.7 have an inability to perceive pain.

Ian: While those individuals with gain of function mutations have non-precipitate as spontaneous severe pain, leading to the identification of Nav1.7 as an important pain-related target, offering the possibility of a new class of pain medicines without the limitations of opioids.

Ian: While other sodium channels involved in the transmission of pain signals, such as NAV1.8, have recently been clinically validated, we believe NAV1.7 has by far the strongest genetic validation.

Ian Mortimer: To date, efforts to develop NAV1.7 inhibitors have faced a number of different challenges, and we have learned a tremendous amount from these previous molecules. We are now advancing novel NAV1.7 inhibitors, which we believe will have the appropriate properties to evaluate the clinical potential of a selective NAV1.7 inhibitor. In this past quarter, we nominated a lead NAV 1.7 candidate, which is expected to enter IND-enabling studies in the near term, with the goal of filing an IND or IND-equivalent in 2025.

Ian: To date, efforts to develop NAV1.7 inhibitors have faced a number of different challenges, and we have learned a tremendous amount from these previous molecules.

Ian: We are now advancing novel NAV1.7 inhibitors, which we believe will have the appropriate properties to evaluate the clinical potential of a selective NAV1.7 inhibitor.

Ian: In this past quarter, we nominated a LEAD NAV 1.7 candidate, which is expected to enter IND-enabling studies in the near term, with the goal of filing an IND or IND-equivalent in 2025.

Ian Mortimer: If successful, this program has the opportunity to generate important and early de-risking human proof of concept. We are also advancing potentiators of the sodium channel NAV1.1, which is based on a scientific rationale that a precision medicine therapy for Dravet syndrome should aim to restore NAV1.1 activity specifically without impacting other neuronal targets. We are pursuing brain penetrant small molecule potentiators with NAV1.1 in an oral dosing formulation, as we believe this approach could directly address the underlying etiology of Dravet syndrome and provide a potential disease-modifying therapy.

Ian: If successful, this program has the opportunity to generate important and early de-risking human proof-of-concept data.

Ian: We are also advancing potentiators of the sodium channel NAV1.1, which is based on a scientific rationale that a precision medicine therapy for Dravet syndrome should aim to restore NAV1.1 activity specifically without impacting other neuronal targets.

Ian: We are pursuing brain penetrant small molecule potentiators with 1.1, in an oral dosing formulation. As we believe, this approach could directly address the underlying ideology of Dravace syndrome and provide a potential disease-modifying therapy.

Ian Mortimer: To round out our extensive CNS discovery work, we continue to make progress as part of our ongoing collaboration with Neurocrine Biosciences to develop treatments for epilepsy. In addition to the ongoing Phase 2 study evaluating MBI-921352 in an orphan pediatric epilepsy, the next lead candidate, a NAV1.2-1.6 inhibitor, is now in IND-enabling studies with the intent to progress into human clinical trials in 2025 as a potential treatment So overall, I'm extremely proud of the continued progress across the organization and our pipeline, including both clinical and preclinical efforts.

Ian: To round out our extensive CNS discovery work, we continue to make progress as part of our ongoing collaboration with Neurocrine Biosciences to develop treatments for epilepsy.

Ian: In addition to the ongoing Phase 2 study evaluating MBI-921352 in an orphaned pediatric epilepsy, the next lead candidate, a NAV1.2-1.6 inhibitor, is now in IND-enabling studies, with the intent to progress...

Ian: and to human clinical trials in 2025 as a potential treatment for epilepsy.

Ian: So overall, I'm extremely proud of the continued progress across the organization and our pipeline, including both clinical and preclinical efforts. In this position, Xenon was one of the most exciting CNS portfolios that exist today.

Ian Mortimer: In this position, Xenon is one of the most exciting CNS portfolios that exist today. So I'll now turn the call over to Chris Kenney, and Chris will provide more detail on the progress on our ZETU calendar clinical programs, as well as some near-term conferences where Xenon will have a presence. Chris, over to you.

Ian: So, I'll now turn the call over to Chris Kenney and Chris will provide more detail on the progress on our Is that you calendar clinical programs, as well as some near-term conferences, where's the known we'll have a presence. Chris, over to you.

Chris Kenney: Thanks a lot, Ian. I'll start by echoing that this is indeed an exciting time at Xenon, as we continue to receive enthusiastic feedback from opinion leaders and site investigators about the emerging clinical profile of Zetucal. Beginning with our Phase III Epilepsy Program, which includes XTOL-2 and XTOL-3 in focal onset seizures and EXACT in primary generalized tonic-clonic seizures, our Phase III FOSS studies continue to advance, with the first top-line data readout from XTOL-2 anticipated in the second half of 2025.

Chris Kenney: Thanks a lot, Ian. I'll start by echoing that this is indeed an exciting time at Xenon, as we continue to receive enthusiastic feedback from opinion leaders and site investigators about the emerging clinical profile for Zetucalamin.

Chris: Beginning with our Phase III Epilepsy Program, which includes XTOL-2 and XTOL-3 in focal onset seizures and exact and primary generalized tonic-clonic seizures,

Ian: Our Phase III FOSS studies continue to advance, with the first top-line data readout from XTOL-2 anticipated in the second half of 2025.

Chris Kenney: Our plan remains to submit results from XTOL 2 along with the existing data package from our Phase 2B XTOL clinical trial and additional safety data from other clinical trials with the goal to meet regulatory requirements in the U.S. for approval. We also continue to highlight the robust scientific evidence generated through the XTOL Open Label Extension Study with the medical community. As Ian referred to, health care providers observe a high burden of illness within the epilepsy community despite current medication.

Ian: Our plan remains to submit results from X-Tool 2 along with the existing data package from our phase to be X-Tool clinical trial and additional safety data from other clinical trials with the goal to meet regulatory requirements in the U.S. for approval.

Ian: We also continue to highlight the robust scientific evidence generated through the external open label extension study with the medical community.

Ian: As Ian referred to, health care providers observe a high burden of illness within the epilepsy community, despite current medications.

Chris Kenney: So it's been important to share the long-term XTOL-OLE data with the objective of gaining further insights on the potential benefits of the Z2 count. We will have additional opportunities to engage with the treatment community at the upcoming European Epilepsy Conference taking place in Rome, Italy, from September 7th to September 11th, where we're presenting two posters on our ongoing XTOL-OLE study, as well as participating in a scientific exhibit where we plan to showcase survey results related to quality of life measures from focal onset seizure, In addition to seizure burden, patients reported other symptoms that illustrate the broad burden of epilepsy and its negative impact on quality of life, such as fatigue, lack of energy, or other comorbidities, including anxiety and depression.

Ian: So, it's been important to share the long-term, external, oily data with the objective of gaining further insights on the potential benefits of the ZETU calendar.

Speaker Change: We will have additional opportunities to engage with the treatment community at the upcoming European Epilepsy Conference taking place in Rome, Italy, from September 7th to September 11th, where we're presenting two posters on our ongoing extol OLE study.

Speaker Change: As well as participating in a scientific exhibit where we plan to showcase survey results related to quality of life measures from focal onset seizure patients.

Speaker Change: In addition to seizure burden, patients reported other symptoms that illustrate the broad burden of epilepsy and its negative impact on quality of life, such as fatigue, lack of energy, or other homework abilities, including anxiety and depression.

Chris Kenney: Moving to progress we're making toward our phase three MDD studies, we have now finalized and filed our protocol with FDA, and clinical site planning is well underway. Our phase three MDD program will include three phase three trials and approximately 450 subjects each with moderate to severe MDD, assessing the efficacy and safety of 20 milligrams of azethucalonib versus placebo. The primary endpoint will be the change from baseline and HAM-D17 total score at week 7. Key secondary endpoints will include SHAP's total score and CGI severity at week 6 and HAM-D17 at week 1.

Speaker Change: Shifting to progress we are making toward our Phase III MDD studies, we have now finalized and filed our protocol with FDA, and clinical site planning is well underway.

Speaker Change: Our Phase 3 MDD program will include 3 Phase 3 trials and approximately 450 subjects each, with moderate to severe MDD, assessing the efficacy and safety of 20 milligrams of a ZETA calendar versus placebo.

Speaker Change: The primary endpoint will be the change from baseline in handy 17 total score at least six.

Speaker Change: T-Secondary Enthorns will include Shapse, Total Score, and CGI severity at Week 6 and Ham the 17 at Week 1. We expect the first MDD study initiation to occur in the second half of the year with study sites exclusively in the U.S.

Chris Kenney: We expect the first MDD study initiation to occur in the second half of the year with study sites exclusively in the U.S. As Ian noted, in addition to this extensive internal planning work, our clinical and medical teams highlighted our phase two proof of concept ex novo trial in patients with MDD at the ASCP meeting in May. This was the first time presenting these data at a major medical meeting, which demonstrated that treatment with Zetucalinerol led to a clinically meaningful reduction in madras, a statistically significant reduction in HMD 17, a rapid onset of effect, a statistically significant reduction in anhedonia, and a potentially differentiated safety profile compared to standard of care age.

Speaker Change: As Ian noted, in addition to this extensive internal planning work, our clinical and medical teams highlighted our Phase 2 Proof of Concept Ex Novo trial in patients with MDD at the ASCP meeting in May.

Ian: This was the first time presenting these data at a major medical meeting.

Speaker Change: which demonstrated that treatment with a Zetu calendar led to a clinically meaningful reduction in Madras.

Speaker Change: A statistically significant reduction in HMD-17, a rapid onset of effect, a statistically significant reduction in anhedonia, and a potentially differentiated safety profile compared to standard of care agents.

Chris Kenney: Feedback on the data was received with great interest by experts in the field. There was recognition of the potential of a Z2 calendar to be a meaningful treatment option for patients with MDD, with particular interest in the novel mechanism of action and potential benefit on anhedonia and a favorable tolerability profile with no notable adverse effect on sexual dysfunction or waking. We're also looking forward to presenting on-core Ex Nova data at the upcoming Psych Congress taking place in Boston from October 29th to November 2nd.

Speaker Change: Feedback on the data was received with great interest by the experts in the field.

Speaker Change: There was recognition of the potential of a Z2 calendar to be a meaningful treatment option for patients with MDD.

Speaker Change: With particular interest in the novel mechanism of action and potential benefit on anhedonia and a favorable tolerability profile with no notable adverse effect on sexual dysfunction or weight gain.

Unknown Attendee: at this time, I would like to welcome everyone to the Q2 2024 Xenon Pharmaceuticals Inc, earnings conference call. All lines have been placed on mute to prevent any background noise.

Speaker Change: We're also looking forward to presenting on core exnova data at the upcoming site Congress taking place in Boston from October 29th to November 2nd.

Chris Kenney: These opportunities to educate healthcare professionals on our MDD data are incredibly important, and we value the insights gained as we further our Zetu-Kaliner clinical program. Now, rounding out my comments on MDD, we also continue to support the investigator-led MDD study conducted by Dr. James Murrow of Mount Sinai and Dr. Sanjay Matthew at the Baylor College of Medicine. This 60-patient placebo-controlled phase 2 trial has a functional primary endpoint with the objective of evaluating the effect of a Z2 calendar on brain measures of reward as measured by the change in activation within the bilateral ventral striatum from baseline to end of treatment at week 8, as assessed by functional MRI.

Unknown Attendee: After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to redraw your question, press star one again. Thank you.

Speaker Change: These opportunities to educate healthcare professionals on our MDD data are incredibly important and we value the insights gained as we further our Z2 calendar clinical programs.

Speaker Change: Now, rounding out my comments on MDD, we also continue to support the investigator-led MDD study conducted by Dr. James Murrow of Mount Sinai and Dr. Sanjay Matthew at the Baylor College of Medicine.

Shad Kuzeret: I would now like to turn the conference over to Mr. Shad Kuzeret, VP, IR First and on. Please go ahead. Good afternoon. Thank you for joining us on our call and webcast to discuss Zenon's second quarter, 2024 financial and operating result. Joining me today are Ian Mortimer, Zenon's president and chief executive officer, Dr. Chris Kenney, Zenon's chief medical officer, and Sherry Aulin, Zenon's chief financial officer. Along with Dr. Chris von Begrins, Zenon's chief commercial officer, who will be available during the Q&A period.

Speaker Change: This 60-patient placebo-controlled Phase 2 trial has a functional primary endpoint with the objective of evaluating the effect of a Z2 calendar on brain measures of reward as measured by the change in activation within the bilateral ventral striatum from baseline to end of treatment at Week 8

Shad Kuzeret: Ian will begin with the summary of our recent progress across our business, including a summary of our expanding preclinical pipeline programs. Chris Kenney will provide an overview of our ongoing clinical stage programs, including our plans and major depressive disorder or MDD, and Sherry will close with a summary of our financial results and anticipated milestones. We will then open a call up for your questions. Please be advised that during this call, we will make a number of questions.

Chris Kenney: Studies are also evaluating secondary clinical endpoints, including the madras and shafts. It is anticipated that patient enrollment will be completed this quarter, and we look forward to providing further updates in the coming months. To summarize, our team is driven to continue advancing our Zetucalendar late-stage clinical development programs in both epilepsy and depression, and we continue to be highly encouraged by the positive response to Zetucalendar from physicians and key opinion leaders. I look forward to updating you on our progress. I'll now turn the call over to Sherry, who will provide an overview of our second quarter financial results and upcoming milestones. Thank you.

Speaker Change: as assessed by functional MRI. The study is also evaluating secondary clinical endpoints including the madras and shaps.

Speaker Change: is anticipated that patient enrollment will be completed this quarter and we look forward to providing further updates in the coming months.

Speaker Change: To summarize, our team is driven to continue advancing our ZETU Calendar late-stage clinical development programs in both epilepsy and depression, and we continue to be highly encouraged by the positive response to ZETU Calendar from physicians and key opinion leaders.

Speaker Change: I look forward to updating you on our progress. I'll turn the call over to Sherry who will provide an overview of our second quarter financial results and upcoming milestones. Sherry?

Sherry Aulin: Great, thank you, Chris. So, beginning briefly with our financial results, we're well positioned with a strong balance sheet to support our plans for AZETU-Kellner in both epilepsy and MDD and other earlier stage programs in our pipeline. As of June 30, 2024, we had cash and cash equivalents and marketable securities of $850.6 million, compared to $930.9 million as of December 31, 2023. Based on our current operating plans, including the completion of the AZETU-Kellner phase three epilepsy studies and fully supporting late stage clinical development of AZETU-Kellner and MDD, we anticipate having sufficient cash to fund operations into 2027.

Sherry: Great, thank you, Chris.

Sherry: So, beginning briefly with our financial results, we're well-positioned with a strong balance sheet to support our plans for AZETU-Kellner in both epilepsy and MDD, and other earlier-stage programs in our pipeline.

Shad Kuzeret: [inaudible] Shad Kuzeret. Thank you, Dr. Shad Kuzeret. [inaudible] The continued execution across our Phase III is at your calendar epilepsy studies. Number two, preparation for our at your calendar MDD program with a focus on finalizing our Phase III protocol and study initiation later this year. And number three, the advancement of our portfolio's next generation eye and channel modulators. Over the last decade, epilepsy research has been a primary focus at Xenon, driven by a continued and significant unmet medical need.

Sherry: As of June 30, 2024, we had cash and cash equivalents and marketable securities of $850.6 million.

Speaker Change: compared to $930.9 million as of December 31, 2023.

Speaker Change: Based on our current operating plans, including the completion of the Zetutelner phase 3 epilepsy studies.

Speaker Change: and fully supporting late-stage clinical development of the Z2 calendar and MDD, we anticipate having sufficient cash to fund operations into 2027. I would refer you to our news release and 10-Q report for further details around our financial results.

Sherry Aulin: I would refer you to our news release and 10-Q report for further details on our financial results. In summary, as you heard from the team today, we remain focused on our goal to improve outcomes for patients in areas of high unmet medical need. We believe that Tukelner has the potential to be a paradigm-shifting best in class medicine. The strong belief in Azetu Kellner's compelling profile is centered around its unique mechanism of action and supported by the significant body of clinical data generated to date.

Speaker Change: So, in summary, as you heard from the team today, we remain focused on our goal to improve outcomes for patients in areas of high and met medical need. We believe that to tell her has the potential to be a paradigm shifting best in class medicine.

Speaker Change: The strong belief in Ezet-U-Kellner's compelling profile is centered around its unique mechanism of action and supported by the significant body of clinical data generated to date. Looking ahead,

Sherry Aulin: Looking ahead, we anticipate a number of important milestone events and goals. We will continue to advance our Reset-to-Calendar Phase 3 epilepsy program with Excel 2 top-line data expected in the second half of 2025. We expect to initiate the first of three phase three clinical trials in MDD in the second half of this year, and we will continue to explore other development opportunities for Z2 Counter. Lastly, we'll continue to advance our early stage preclinical pipeline with the goal of filing multiple INDs or equivalent in 2025.

Speaker Change: We anticipate a number of important milestone events and goals.

Speaker Change: We will continue to advance the Rosetta Kellner Phase 3 Epilepsy Program, with Excel 2 top-line data expected in the second half of 2025.

Speaker Change: We expect to initiate the first of three phase three clinical trials in MDD in the second half of this year.

Speaker Change: and we will continue to explore other development opportunities for ZET to calendar. Lastly, we'll continue to advance our early stage pre-clinical pipeline with the goal of filing multiple I&Ds or equivalent in 2025.

Shad Kuzeret: With many patients still struggling to control focal onset seizures and primary generalized tonal chronic seizures despite available medications. For that reason, the continued progress of a Zetu Kellner in our broad phase 3 epilepsy program remains core to our business. As a reminder, Zetu Kellner is the only KV7 potassium channel opener in development with phase 2B efficacy and long-term safety data in epilepsy patients. No other KV7 molecules in development have efficacy and safety data in epilepsy or depression patients.

Sherry Aulin: Thank you all today for your attention, and we look forward to sharing more in the coming months. I'll now ask the operator to open the line for any questions. Thank you. The floor is now open for questions. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question,

Speaker Change: Thank you all today for your attention and we look forward to sharing more in the coming months. I'll now ask the operator to open the line for any questions.

Unknown Speaker: Thanks, Paul. I'll take the second one and maybe make a quick comment on the first one.

Operator: Thank you. The floor is now open for questions. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star 1 again. If you are called upon to ask your question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. And if your first question comes from the line of Paul Matteis with Stifel, please go ahead.

Speaker Change: Thank you. The floor is now open for questions. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue.

Speaker Change: If you would like to withdraw your question, simply press star 1 again. If you are called upon to ask your question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question.

Shad Kuzeret: And we have set an incredibly high bar for other KV drugs and development to achieve the impressive attributes of a Zetu Kellner. Data from our phase 2B X-Tool epilepsy trial demonstrated the best placebo-adjusted clinical efficacy in the most refractory patient population ever trialled, as well as a favorable tolerability profile in adaptations with focal onset seizures. Furthermore, long-term efficacy data generated through our X-Tool open label extension support increased seizure reduction, with patients out to 30 months on a Zetu Kellner showing a greater than 90% reduction in median monthly seizure frequency, while approximately 1 in 4 patients on a Zetu Kellner for at least 2 years have been seizure-free for a full year or longer.

Speaker Change: And your first question comes from the line of Paul Matteis with Stifel. Please go ahead.

Paul Matteis: Hey there, good afternoon, congrats on all the progress.

Paul Matteis: As it relates to Exxon 2, I was wondering if by now you have a good sense of how the patient demographics...

Speaker Change: As it relates to baseline seizure frequency, refractoriness, et cetera, comparing...

Speaker Change: to XTOL 1. And then just as it relates to your updated timing guidance for top line, thanks for that. Is the expectation still that you'll complete enrollment around the end of this year, early next year? Thanks so much.

Unknown Speaker: And Chris Kenney, if you want to add any of your perspective as well. So on the first question, just on demographics, so obviously, we track that; we see it on a blinded basis. And all the things that you'd expect us to track, we're looking at on a blinded basis. You know, we haven't historically given any information publicly on what we're seeing, just because, as the study is ongoing, those demographic data are changing all the time.

Speaker Change: Thanks, Paul. I'll take the second one and maybe make a quick comment on the first one, then Chris Kenney, if you want to add any of your perspective as well. So on the first question, just on demographics, so obviously we track that, we see it on a blinded basis,

Shad Kuzeret: In addition, we now have over 600 patient years of exposure, as well as patients on a Zetu Kellner for more than 4 years in the OLE, giving us and the epilepsy community tremendous confidence around the future potential of a Zetu Kellner to address the need for new anti-seizure medication. With that in mind, we continue to progress patient enrollment across our ongoing phase 3 epilepsy studies, with top line results from X-Tool II in focal onset seizures anticipated in the second half of 2025. Positive results would enable the submission of our NDA with the goal of advancing Zetu Kellner towards commercialization.

Speaker Change: and all the things that you'd expect us to track, we're looking at.

Speaker Change: on a blinded basis. You know, we haven't historically.

Chris Kenney: Given any information publicly on what we're seeing just because as the study is ongoing those demographic data are changing all the time So but we are we're definitely tracking that. So as we get to the end of patient screening in Randomization we can be in a position to give some of that information publicly, but Chris can add

Unknown Speaker: But we are definitely tracking it. So as we get to the end of patient screening and randomization, we can, we'd be in a position to give some of that information publicly. But Chris can add a minute there also.

Chris Kenney: In a minute there also. Yeah, and then in terms of guidance, I think you've kind of nailed it. We've moved to top line data guidance now. So just to reiterate, I know we said it a few times, but XTOL 2 top line guidance, second half of next year, you know, just to take a step back, I think we've said it before, it's about six to eight months

Ian Mortimer: Overall, we are very pleased with the progress in our phase 3 program, and is exciting to be in a position to develop what we believe will be the next important medicine to treat patients with focal epilepsy, focusing now on our Zetu Kellner MDD program, we recently presented the phase 2 Xnova trial results at the American Society of Clinical Psychopharmacology, where SCP, the annual meeting held in Miami and May. This medical meeting was a great opportunity for us to continue to raise awareness of data supporting Zetu Kellner's potential differentiated profile versus standard care agents and MDD, including a rapid onset of effects.

Chris Kenney: Yeah, and then in terms of guidance, I think you've kind of nailed it; we've moved to top line data guidance now. So just to reiterate, I know we said it a few times, but XTOL 2 top line guidance, second half of next year. Just to take a step back, I think we've said it before, it's about six to eight months from last patient screened to top line data. And that's because these patients go through a screening period.

Chris Kenney: from last patient's screen to top-line data. And that's because these patients go through a screening period.

Chris Kenney: And then there's a two month baseline period where they have to count seizures in an electronic diary so that we can come up with a monthly seizure burden. Then the randomization visit happens, and there are three months of the double-blind period. And then there is safety follow-up. That safety follow-up. The timing depends a little bit on whether those last patients go into open label extension or not. So, you know, just kind of back all that out, you know, where exactly screening will complete. We're comfortable with our guidance on second half data, which means that you kind of back out six to eight months from that is when we expect patient screening to be completed.

Chris Kenney: And then there's a two-month...

Chris Kenney: The baseline period where they have to count seizures in an electronic diary, that's we can come up with a monthly seizure burden. Then the randomization visit happens and there's three months.

Chris Kenney: of the double-blind period, and then there is safety follow-up. That safety follow-up, the timing depends a little bit on whether those last patients go into open-label extension or not. So, you know, just to kind of back all that out, you know, where exactly screening will complete, you know, we're comfortable with our guidance of second-half data, which means that you kind of back out six to eight months from that is when we expect patient screening to be completed.

Ian Mortimer: Tolerable safety profile, and a potential benefit on anhedonia, a common comorbidity with a significant unmet need. These data form the basis of our decision to advance Zetu Kellner into a phase 3 program in MDD, which we expect to initiate in the second half of this year. We are also continuing to evaluate additional clinical development opportunities for Zetu Kellner, focusing specifically on other neuropsychiatric indications, where a scientific rationale exists, as well as a commercial fit with epilepsy and MDD.

Chris Kenney: So hopefully, that just gives a little bit more background and color on kind of the process that we're going through. Chris, anything else on the demographics that you want to comment on? Yeah, so just as a reminder, the seizure burden

Chris Kenney: So, also, that just gives a little bit more background and color on kind of the process that we're going through. Chris, anything else on the demographics that you want to comment on?

Chris Kenney: And despite that, we saw really robust efficacy with the largest separation between the high dose and placebo from the perspective of median percent change in seizure frequency compared to any other study we could find in focal onset seizures. So we're pretty pleased with that. So the spirit of the subsequent Phase 3 program is to do the best you can to not deviate from what was done in XTOL because that worked out pretty well.

Chris Kenney: Yeah, so just as a reminder, the seizure burden in the X-Toll Phase 2B study was pretty high. Patients had an average of 13 and a half seizures per month at baseline, half the population was taking three anti-seizure medications, and on average, patients had failed six anti-seizure medications even before coming into the study.

Chris Kenney: So just as a reminder, the seizure burden in the X-Toll Phase 2B study was pretty high.

Ian Mortimer: Beyond Zetu Kellner, we continue to expand Zenon's leadership in the small molecule ion channels. Space, based on our extensive work in channel opacies over the past two decades, as we built out a world-class discovery team. We have recently expanded our pipeline by nominating multiple development track candidates or DTCs targeting potassium and sodium channels. Achieving DTC status is a critical milestone for a program, as it reflects the molecule that has met our rigorous criteria to be advanced into GLP toxicology studies, and if successful, we'll form the basis of an IMD or IMD equivalent submission.

Chris Kenney: Patients had an average of 13.5 seizures per month at baseline. Half the population were taking three anti-seizure medications.

Speaker Change: and on average patients had failed six anti-season meditations even before coming into the study. And despite that, we saw a really robust efficacy with the largest separation between the high dose and placebo.

Chris Kenney: from the perspective of median percent change in seizure frequency compared to any other study we can find in focal onset seizures.

Chris Kenney: So we're pretty pleased with that. So the spirit of the subsequent phase three program is

Ian Mortimer: One of our key areas of focus for potassium channels, as we believe KV7 offers potential pipeline in a mechanism opportunities. The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional KV7 product candidates that are chemically diverse from a Zetu calendar and can provide additional development opportunities across a broad range of therapeutic indications, including seizure disorders, pain, and neuropsychiatric conditions. For that reason, we continue to advance multiple KV7 molecules so that we can potentially extend the reach of this promising and differentiated mechanism to more patients in need.

Chris Kenney: And so that's what we've tried to do. And more directly as an answer to the question, what we're seeing so far is that the population has shaped up very similarly in the Phase 3 program as it did in the Phase 2 study. And obviously, we're keeping an eye on that in real time. It gives you the opportunity to make an adjustment if you have to, if you were getting something unexpected, but we're not right now.

Speaker Change: Do the best you can to not deviate from what was done in EXTOL because that worked out pretty well. And so that's what we've tried to do. And more directly, as an answer to the question, what we're seeing so far is that the population has shaped up very similarly in the Phase 3 program as it did in the Phase 2 study. And obviously we're keeping an eye on that in real time. Gives the opportunity to make an adjustment if you had to if you were getting something unexpected, but we're not right now.

Speaker Change: Good to hear. All right, thank you both very much.

Chris Kenney: Oh!

Operator: Your next question comes from the line of Brian Abrahams with RBC Capital Markets. Please go ahead.

Brian Everham's: Your next question comes from the line of Brian Everham's with RBC Capital Markets. Please go ahead.

Unknown Speaker: Hey, it's a late go on for Brian. Thanks for taking my question. I had maybe one and then just a quick clarifying question as well. I guess on the MDD trial design, I guess as you're thinking about how Zetecal or my position itself, and there's a number of other agents that are also potentially having effects on anhedonia, I guess, as those other competitive trials, and I think of the capi-opioid start to read out, I guess, are you looking for any data there and how they perform on anhedonia to maybe inform and whether you want to change selection for anhedonia or how that might impact market positioning for Zetecal?

Ian Mortimer: Building on our extensive experience against the KV7 target developed over many years, we have made significant progress across several promising novel chemical series, and this past quarter, we nominated multiple KV7 development track candidates with a lead candidate now in IMD enabling studies to support our goal of filing an IMD or IMD equivalent in 2025. We believe these advancements in our KV7 preclinical program combined with the promising and robust clinical data we have generated to date with a Zetu calendar in epilepsy and MDD, set Zenon at that forefront of both drug discovery and development for this important mechanism.

Brian Everham's: It's a late one for Brian. Thanks for taking my question. I had maybe one and then just a quick clarifying question as well I guess on the MDD trial design I guess as you're thinking about how the decaler might position itself, and there's a number of other agents that are also potentially having effects on Anidonia, I guess as those other competitive trials, and I think of the Cappy Opioid start to read out, I guess

Chris Kenney: Are you looking for any data there and how they perform on an addoni to maybe inform and whether you want to change selection for an addoni or how that might impact market positioning for as it's a counter and then just to clarify it. I think you guys said that you're not running XUS sites for the MDD.

Unknown Speaker: And then just to clarify, I think you guys said that you're not running ex-US sites for the MDD phase three program. And I think maybe before you had said that you would use both international and US sites. Can you maybe talk about what drove that change, if I heard you guys correctly, and maybe how that might impact many expectations on timing and how quickly you can move? Thanks.

Ian Mortimer: Turning now to our sodium channel work. As an early pioneer in the space, Zenon scientists focus on identifying genetic targets associated with rare phenotypes. Through this early work, it was uncovered that individuals with complete loss of function mutations in the gene encoding for Nav1.7 have an inability to perceive pain. While those individuals with gain-of-function mutations have non precipitateous spontaneous severe pain, lean to the identification of Nav1.7 as an important pain-related target, offering the possibility of a new class of pain medicines without the limitations of opioids.

Speaker Change: Thank you for joining us for today's phase three program, and I think maybe before you had said that you would use both international and U.S. sites, I guess. Can you maybe talk about what drove that change, if I heard you guys correctly, and maybe how that might impact many expectations on timing and how quickly you can move? Thanks.

Unknown Speaker: Thanks Leo. I can start and then Chris Kenney can add in on the MDD side.

Speaker Change: Thanks Leo. I can start and then Chris Kenney to add in on the MDD side. And Chris von Seggern, if you can provide perspective a little bit about the market and what we're hearing back in our market research and the importance of Anhedonia and maybe how we believe

Unknown Speaker: And Chris von Seggern, could you provide perspective a little bit about the market and what we're hearing back from our market research and the importance of anhedonia and maybe how we believe Zetecaliner can differentiate with some of the other molecules both in development but also those that are commercially available currently? So a couple of comments. Yeah, just on clarification in terms of the ex-U.S. U.S. sites, we've said that, you know, we're running three phase three clinical trials in depression.

Speaker Change: Is that to count or can differentiate with with some of the other molecules both in development, but also those that are commercially available currently?

Ian Mortimer: While other sodium channels involved in the transmission of pain signals such as Nav1.8 have recently been clinically validated, we believe Nav1.7 has by far the strongest genetic validation. To date, efforts to develop Nav1.7 inhibitors have faced a number of different challenges and we have learned a tremendous amount from these previous molecules. We are now advancing novel Nav1.7 inhibitors which we believe will have the appropriate properties to evaluate the clinical potential of a selective Nav1.7 inhibitor.

Speaker Change: So, a couple of comments, yeah, just on clarification in terms of the ex-US, US sites.

Speaker Change: We've said that, you know, we're running three phase three clinical trials in depression. We had always, this isn't a change. We had always expected that definitely the first study, which will start in the next couple of months.

Unknown Speaker: We had always, this isn't a change, we had always expected that definitely the first study, which will start in the next couple of months, would focus on U.S. sites. As we get to the second and the third studies, we may move to some ex-U.S. sites. But right now, that's where phase two is being run. I think that's where a lot of the clinical development for major depressive disorder is done in the U.S.

Speaker Change: would focus on U.S. sites. As we get to the second and the third...

Speaker Change: Studies, we may move to some XUS sites, but right now, that's where the Phase 2 is run. I think that's where a lot of the clinical development for major depressive disorders done in the US. So we'll definitely focus that for Act will work all in X Nova 2, which is the first Phase 3.

Ian Mortimer: In this past quarter, we nominated a lead Nav1.7 candidate, which is expected to enter IND enabling studies in the near term with the goal of filing an IND or IND equivalent in 2025. 5. If successful, this program has the opportunity to generate important and early de-risking human proof of concept data. We are also advancing potentiators of the sodium channel nav 1.1, which is based on a scientific rationale that a precision medicine therapy for drove a syndrome should aim to restore nav 1.1 activity, specifically without impacting other neuronal targets.

Unknown Speaker: So we'll definitely focus on that for what we're calling ex-NOVA2, which is the first phase three. And then as we move into the other phase threes, there may be some differences in site selection as we move forward. So hopefully that helps, you know, in terms of the protocol, you know, how we may be informed by other readouts. You know, the protocol for us in the MDD study is locked. So, as Chris said in his prepared remarks, we have filed the phase three protocol with the FDA.

Speaker Change: And then as we move into the other phase threes, there may be some difference in site selection as we move forward.

Chris Kenney: So, hopefully, that helps. You know, in terms of the protocol, you know, how we may be informed by other readouts. You know, the protocol for us in the NDD study is locked, so we as Chris said in his prepared remarks.

Chris Kenney: We have filed the phase 3 protocol to the...

Unknown Speaker: We expect to hear back shortly on that and initiate that study. So, in terms of the inclusion and exclusion criteria, as it relates to baseline, both depression and anhedonia, all of that stuff is now locked. And as we said on previous calls, I think we're very much informed by our phase two program using MD-17 as primary and also increasing the severity of the patients as we move from phase two to phase three.

Chris Kenney: With the FDA, we expect to hear back.

Ian Mortimer: We are pursuing brain penetrant small molecule potentiators with nav 1.1, in an oral dosing formulation, as we believe this approach could directly address the underlying etiology of drove a syndrome and provide a potential disease modifying therapy. Around our extensive CNS discovery work, we continue to make progress as part of our ongoing collaboration with neurocran biosciences to develop treatments for epilepsy. In addition to the ongoing phase 2 study, evaluating MBI 921352 in an orphan pediatric epilepsy, the next lead candidate, a nav 1.21.6 inhibitor, is now in I&D enabling studies with the intent to progress into human clinical trials in 2025 as a potential treatment for epilepsy.

Chris Kenney: Shortly on that and initiate that study, so in terms of the inclusion exclusion criteria, as it relates to baseline.

Chris Kenney: both depression and anhedonia, all of that stuff is now locked. And as we said on previous calls, I think we're very much informed.

Chris Kenney: by our Phase 2 program using MD-17 as primary and also increasing the severity of the patients as we move from Phase 2 to Phase 3. So, although I think, you know, additional readouts are always interesting, they're not going to change in terms of our strategy or approach. But Chris Kenney, why don't you add to that and then Chris von Seggern on just differentiation in the marketplace.

Unknown Speaker: So although I think, you know, additional readouts are always interesting, they're not going to change terms of our strategy or approach. But Chris Kenny, why don't you add to that? And then Chris von Sager on just differentiation in the marketplace.

Chris Kenney: Yeah, I would just zoom out from anhedonia for a second. I think why this, why is your calendar so interesting, and MDD is really kind of a constellation of features, not just anhedonia. So we've got the unique mechanism of action, we have the rapidity of onset, which also happens in focal onset seizure patients, which makes you think it may be real. And then the safety.

Chris Kenney: [inaudible]

Chris Kenney: Yeah, I would just, just zooming out from Anhedonia for a second, I think why this

Chris Kenney: Why is that your calendar so interesting and MDD is really kind of a constellation of features not just anhedonia so we've got the the unique mechanism of action we have the rapidity of onset which also happened in focal onset seizure patients which makes you think it's it may be real

Ian Mortimer: So overall, I'm extremely proud of the continued progress across the organization and our pipeline, including both clinical and preclinical efforts. In this position, Xenon was one of the most exciting CNS portfolios that exist today.

Chris Kenney: So I'll now turn the call over to Chris Kenney, and Chris will provide more detail on the progress on our, is that you count our clinical programs, as well as some near-term conferences, where Xenon will have a presence. Chris, over to you. Thanks a lot Ian.

Chris Kenney: and then the safety. So on the safety side from an MDD perspective we had

Chris von Seggern: So on the safety side, from an MDD perspective, we had, you know, no notable issues with sexual side effects or weight gain. And in fact, the drug at 20 milligrams was better tolerated in the MDD population compared to the focal onset seizure population. So, you know, that safety tolerability data, no SAEs in any of the 10 or 20 milligram treatment groups in ex nova, that is, I think it's important or perhaps even more so, but I would say it's more the constellation of all those features, not one per se, and maybe I'll turn it to Chris to see if he can give his perspective from the commercial perspective. Yeah, thanks, Chris. So, maybe just I should just

Chris Kenney: You know, no notable issues with sexual side effects or weight gain, and in fact, the drug at 20 milligrams.

Chris Kenney: was better tolerated in the MDD population compared to the focal length that seizure population. So, you know, that safety-tolerability data, no SAE is in any of the 10 or 20 milligram treatment groups in Exnova. That is, I think it's...

Chris Kenney: I'll start by echoing that this is indeed an exciting time at Xenon, as we continue to receive enthusiastic feedback from opinion leaders and site investigators about the emerging clinical profile for Zetu Calmer. Beginning with our phase 3 epilepsy program, which includes X-122 and X-123 and focal onset seizures, and exact and primary generalized toniconic seizures, are phase 3 foster studies continued to advance, with the first top line data readout from X-122 anticipated in the second half of 2025.

Chris Kenney: You know is important or perhaps even more so, but I would think it's more the constellation of all those features not one per se and Maybe I'll turn it to Chris to see if he what his perspective is from the commercial perspective

Chris von Seggern: Yeah, thanks, Chris. So maybe just to ground everyone, when we think about the major depressive disorder treatment landscape, it's important to note that the mainstay of treatment in this space, SSRIs and SNRIs, notably do not have a benefit, specifically on the anhedonia component of the disorder. And when we conduct our market research, as we think ahead towards commercializing the ascetic calendar and major depressive disorder, clinicians have very clearly identified anhedonia as one of those constellation of features that Chris Kenney mentioned, but also the fact that having a benefit in this core symptom domain or comorbidity of major depressive disorder is something that is very, very encouraging.

Chris Kenney: Yeah, thanks, Chris. So maybe just to ground everyone when we think about

Chris Kenney: It's important to note that the mainstay of treatment in this space, SSRIs, SNRIs, notably do not have a benefit specifically on the anhedonia component of the disorder. And when we conduct our market research, as we think ahead towards commercializing azethucalin or major depressive disorder, clinicians have very clearly identified anhedonia as a

Chris Kenney: Our plan remains to submit results from X-122 along with the existing data package from our phase 2B X-122 clinical trial and additional safety data from other clinical trials, with the goal to meet regulatory requirements in the US for approval. We also continue to highlight the robust scientific evidence generated through the X-12 open label extension study with the medical community. As Ian referred to, healthcare providers observe a high burden of illness within the epilepsy community, despite current medications. So it's been important to share the long-term X-12 OLED data with the objective of gaining further insights on the potential benefits of the Zetu Calmer.

Chris Kenney: One of those constellation of features that Chris Kenney mentioned, but also the fact that having a benefit in this core symptom domain or comorbidity of major depressive disorder is something that is very, very encouraging. And clinicians are actively looking for, given the fact that the SSRIs and SNRIs don't provide benefit along that dimension. So when we do our research and we do our testing of a potential Zeta Calendar profile, it's something that clinicians absolutely latch on to, and appreciating that folks are now focused on this area in large part because of the unmet medical need that exists in the marketplace today.

Chris von Seggern: And clinicians are actively looking for, given the fact that SSRIs and SNRIs don't provide benefit along that dimension. So when we do our research and we do our testing of a potential ascetic calendar profile, it's something that clinicians absolutely latch onto in appreciating that folks are now focused on this area in large part because of the unmet medical need that exists in the marketplace today.

Chris Kenney: We will have additional opportunities to engage with the treatment community at the upcoming European epilepsy conference taking place in Rome, Italy from September 7th to September 11th, where we're presenting two posters on our ongoing X-12 OLED study, as well as participating in a scientific exhibit where we plan to showcase survey results related to quality of life measures from focal onset seizures, of patients. In addition to seizure burden, patients reported other symptoms that illustrate the broad burden of epilepsy and its negative impact on quality of life, such as fatigue, lack of energy, or other coma or disease, including anxiety and depression.

Chris Kenney: [inaudible]

Unknown Speaker: Thanks, Chris. Operator, we can move to the next question.

Speaker Change: Lecture Operator, we can move to the next question.

Operator: Again, if you would like to ask a question, press star 1 on your telephone keypad. Your next question comes from the line of Tessa Romero with JP Morgan. Please go ahead.

Speaker Change: Again, if you would like to ask a question, press star 1 on your telephone keypad. Your next question comes from the line of Tessa Romero with JP Morgan. Please go ahead.

Ian Mortimer: Good afternoon. Thank you for taking our question. So, Ian, you've outlined Topline XL2 data for the second half of 2025 here. Thinking back on an earlier question that was asked, maybe asked slightly differently, can you just provide a little bit of an updated view for us on how the pace of enrollment has been going? And, you know, just kind of curious; has it been pretty steady since all the sites were activated?

Chris Kenney: Shifting to progress we're making toward our Phase 3 MDD studies, we have now finalized and filed our protocol with FDA and clinical site planning is well underway. Our Phase 3 MDD program will include three Phase 3 trials, and approximately 450 subjects each, with moderate to severe MDD, assessing the efficacy and safety of 20 milligrams of the Zetu calendar versus placebo. The primary endpoint will be the change from baseline in HMD 17 total score at week six.

Tessa Romero: Good afternoon. Thank you for taking our question. So Ian, you've outlined top-line XO2 data in the second half of 2025 here.

Speaker Change: Thinking back up on like an earlier question that was asked, maybe asked slightly differently. And you just provide a little bit of an updated view for us on how the pace of enrollment has been going. And you know, just how curious has it been pretty steady since...

Ian Mortimer: Have you observed any changes due to competitive dynamics or anything else here in the U.S. or globally across sites? And can you just remind us what the split is between U.S. and ex-U.S. sites and what the key regions outside the U.S. are? Thanks so much.

Speaker Change: All the sites were activated, or are there, have you observed any changes due to competitive dynamics or anything out here in the US or globally across sites?

Chris Kenney: Key secondary endpoints will include Shaps total score and CGI severity at week six and HMD 17 at week one. We expect the first MDD study initiation to occur in the second half of the year with study sites exclusively in the U.S.

Ian Mortimer: Thanks, Tess. Yeah, I think I've got it all, but others can jump in if I've missed something. So, yeah, in terms of, you know, pace of enrollment and kind of top line guidance, as you said, top line for XTOL 2, second half 25, I think that's really exciting for us, right? I mean, that's a critical path now. With the data from XTOL, and with XTOL 2, we'll be ready to engage with FDA and file an NDA.

Speaker Change: Thanks, Tess. Yeah, I think I've got it all, but...

Speaker Change: others can jump in if I've missed something so

Chris Kenney: As Ian noted, in addition to this extensive internal planning work, our clinical and medical teams highlighted our Phase 2 proof of concept ex-novertrial in patients with MDD at the ASCP meeting in May. This was the first time presenting these data at a major medical meeting, which demonstrated the treatment with a Zetu calendar led to a clinically meaningful reduction in Modress, a statistically significant reduction in HMD 17, a rapid onset of effect, a statistically significant reduction in Amidonia, and a potentially differentiated safety profile compared to standard of care agents.

Speaker Change: Yeah, in terms of, you know, pace of enrollment and kind of top-line guidance, as you said, top-line for XTOL 2, second half 25, I think that's really exciting for us, right? I mean, that's a critical path now. With the data from XTOL, with XTOL 2, we'll be ready to engage with FDA and file an NDA, so that's really exciting now to have that top-line.

Ian Mortimer: So that's really exciting now to have that top line data guidance out. In terms of the cadence or pace of enrollment, you know, we said on previous calls that just the number of sites that you need to complete these studies, which is kind of in, you know, 100 medical centers, give or take, in each of X-Hole 2 and X-Hole 3, you just naturally do get some ebb and flow and up and down in enrollment.

Speaker Change: Data Guidance Out. In terms of cadence or pace of enrollment, you know, we said on previous calls that just the number of sites that you need to complete these studies, which is kind of in, you know, 100 medical centers, give or take,

Speaker Change: In each of X-Tool 2 and X-Tool 3 is that you just naturally do get some Evan's flow and up and down of enrollment. So we've been comfortable with where we are and we're comfortable with the guidance that we're giving and obviously we have more experience in running these types of studies than anybody else out there right now, so I think we're in really good shape.

Chris Kenney: Feedback on the data was received with great interest by the experts in the field. There was recognition of the potential of a Zetu calendar to be a meaningful treatment option for patients with MDD, with particular interest in the novel mechanism of action and potential benefit on Anadonia and a favorable tolerability profile with no notable adverse effect on sexual dysfunction or weight gain.

Ian Mortimer: So we're comfortable with where we are, and we're comfortable with the guidance that we're giving. And, you know, obviously, we have more experience running these types of studies than anybody else out there right now. So I think we're in really good shape.

Ian Mortimer: You know, in terms of competitive pressures, we haven't seen anything. So we haven't seen the pace of enrollment change from a competitive perspective. We're, you know, obviously, when we were running X-Hole, there were at times other studies that were being run, and the same thing when you're running, when we're running X-Hole 2. And that's not just all, you know, I think your question is probably a little bit more focused on drug trials, but there are device studies as well that are ongoing. So there are always other things that are happening often at these clinical centers, but we haven't really seen any change in the last little while that has given us any pause or any concern.

Speaker Change: In terms of competitive pressures, we haven't seen anything, so we haven't seen the pace of enrollment change from a competitive perspective.

Chris Kenney: We're also looking forward to presenting on core ex-novert data at the upcoming site Congress taking place in Boston from October 29th to November 2nd. These opportunities to educate healthcare professionals on our MDD data are incredibly important, and we value the insights gained as we further our Zetu calendar clinical programs. Now, rounding out my comments on MDD, we also continue to support the investigator-led MDD study conducted by Dr. James Murrow of Mount Sinai and Dr. Sanjay Matthew at the Baylor College of Medicine.

Speaker Change: We're, you know, obviously, you know, when we were running next to all, there's that times other studies that are being run and the same thing when you're running.

Speaker Change: And that's not just all, you know, I think your questions probably a little bit more focused on drug trials, but there's device studies as well that are ongoing. So there's always other things that are happening often at these clinical centers.

Ian Mortimer: In terms of regions, so X-Hole 2, we've really tried to use X-Hole as much as our guides. We went back to a lot of the same centers from X-Hole into X-Hole 2 and use investigators that have experience with the molecule. As a reminder, in the X-Hole Phase 2 study, we had sites, clinical sites in Europe and clinical sites in the U.S. At the end of the day, 60% of patient enrollment came from Europe and 40% came from the U.S. Again, you know, while we're partway through a study, I don't really want to comment on where we're coming from in X-Hole 2, but the same jurisdictions that we used in X-Hole, we're using in X-Hole 2.

Speaker Change: In the last little while that is given us any pause of any concern.

Chris Kenney: This 60-patient placebo-controlled Phase 2 trial has a functional primary endpoint with the objective of evaluating the effect of a Zetu calendar on brain measures of reward as measured by the change in activation within the bilateral ventral strideum from baseline to end of treatment at week eight as assessed by functional MRI. The study is also evaluating secondary clinical endpoints, including the modus and shafts.

Speaker Change: In terms of regions, so EXTOL 2, we've really tried to use EXTOL as much as our guides. We went back to a lot of the same centers from EXTOL into EXTOL 2 and used investigators that have experience.

Speaker Change: with the molecule. As a reminder, in the X-Tool Phase 2 study, we had sites, clinical sites in Europe and clinical sites in the U.S.

Speaker Change: At the end of the day, 60% of patient enrollment came from Europe and 40% came from the U.S. Again, while we're partway through a study, I don't really want to comment on where we're coming from in XTOL 2, but the same jurisdictions that we used in XTOL, we're using in XTOL 2.

Chris Kenney: It is anticipated that patient enrollment will be completed this quarter, and we look forward to providing further updates in the To summarize, our team is driven to continue advancing our Zetu Calendar late stage clinical development programs in both epilepsy and depression, and we continue to be highly encouraged by the positive response to Zetu Calendar from physicians and key opinion leaders. I look forward to updating you on our progress.

Operator: I think I've got all of your questions answered there, but if there's anything else, please let me know. You did. Thanks so much.

Operator: You did. Thanks so much, Ian. Talk to you soon. Thank you, Tessa.

Speaker Change: I think I got all of your questions that are, but if there's anything else, please let me know.

Speaker Change: Thank you so much, Ian. Thank you so much.

Operator: Again, if you would like to ask a question, press star 1 on your telephone keypad. Your next question comes from the line of Jason Gerberry with Bank of America. Please go ahead.

Sherry Aulin: I'll now turn the call over to Sherry who will provide an overview of our second quarter financial results and upcoming milestones. Sherry? Great. Thank you, Chris. So beginning briefly with our financial results, we're well positioned with a strong balance sheet to support our plans for Zetu Calendar in both epilepsy and MDD and other earlier stage programs in our pipeline. As of June 30th, 2024, we had cash and cash equivalents and marketable securities of 850.6 million compared to 30.9 million as of December 31st, 2023.

Speaker Change: Again, if you would like to ask a question, press star one on your telephone keypad. Your next question comes from the line of J. Sue Gerberi with Bank of America. Please go ahead.

Sherry Aulin: Based on our current operating plans, including the completion of the Zetu Calendar phase three epilepsy studies and fully supporting late stage clinical development of a Zetu Calendar and MDD, we anticipate having sufficient cash to fund operations into 2027. I would refer you to our news release and 10 key report for further details around our financial results.

Operator: Hi, good afternoon. This is Dina on behalf of Jason.

Speaker Change: Hi, good afternoon, this is Gina on for Jason. Thank you so much for taking our question. We just wanted to ask about the next.

Speaker Change: Generation KV7 asset. That's an IND enabling studies. Could you please provide some more color on the specific drug properties that led you to advance this asset?

Unknown Speaker: Thank you so much for taking our question. We just wanted to ask about the next generation KD7 asset that's in IND enabling studies. Could you please provide some more color on the specific drug properties that led you to advance this asset? Is your aim to improve upon, as it is Kulnar's profile, or is this more of a life cycle management play to advance KD7 into neuropsych opportunities beyond the current epilepsy and MDD set?

Speaker Change: Is your aim to improve upon, as it took Kolnar's profile, or is this more of a life cycle management play to advance KD7 into neuropsych opportunities beyond the current, you know, epilepsy and MDD set?

Ian Mortimer: Thanks, Dina. Yeah, I think it's a really important question. Obviously, the success we've had with azethutaliner, now in late stage clinical development, we think it's really important for us to continue to maintain and build upon what we think is really a considerable leadership position in this mechanism, which we're really excited about. So we've been working on additional molecules against the same target for quite some time. So they are completely diverse chemistries from azethutaliner.

Speaker Change: Thank you.

Speaker Change: Thanks, Dina. Yeah, I think it's a really important question, obviously.

Sherry Aulin: So in summary, as you heard from the team today, we remain focused on our goal to improve outcomes for patients in areas of high unmet medical need. We believe that Zetu Calendar has the potential to be a paradigm shifting best in class medicine. The strong belief in a Zetu Calendar's compelling profile is centered around its unique mechanism of action and supported by the significant body of clinical data generated to date.

Speaker Change: The success we've had with Zetecaliner now in late stage clinical development, we think it's really important for us to continue to maintain and build.

Speaker Change: Upon what we think is really a considerable leadership position in this mechanism which we're really excited about.

Speaker Change: So we've been working on additional molecules.

Speaker Change: against the same target for quite some time. So completely diverse chemistries from a Z2 calendar. As you mentioned, and we said in our prepared remarks, multiple candidates have been identified.

Ian Mortimer: As you mentioned, in our prepared remarks, multiple candidates have been identified, including the lead one in GLP toxicology studies. So we're excited to get that into human clinical development as well. You know, we touched upon what we call our DTC, or development track candidate, and you asked the question about drug properties. It's quite a long list of things that we try to optimize all of these drugs for, obviously, potency and selectivity on target, but a bunch of other drug properties as well.

Sherry Aulin: Looking ahead, we anticipate a number of important milestone events and goals. We will continue to advance our Zetu Calendar phase three epilepsy program with X-Tool-2 top line data expected in the second half of 2025. We expect to initiate the first of three phase three clinical trials and MDD in the second half of this year and we will continue to explore other development opportunities for Zetu Calendar. Lastly, we will continue to advance our early stage preclinical pipeline with the goal of filing multiple INDs or equivalent in 2025.

Speaker Change: including the lead one is in GLP toxicology studies so we're excited to get that into human clinical development as well. You know we touched upon what we call our DTC or development track candidate and you asked the question around product drug properties

Speaker Change: It's a quite a long list of things that we try to optimize all of these drugs for. Obviously potency and selectivity on target, but a bunch of the drug properties as well.

Ian Mortimer: So what's really interesting about azethutaliner is there isn't any one specific attribute of azethutaliner that we're trying to improve on. Right now, as we've gone through the data, as we've mentioned, this is the best in category efficacy on a placebo-adjusted basis, the novel mechanism, the rapidity of onset. So we think we have so many of the important attributes to be successful, both in epilepsy and depression, that these next generation molecules, which have diverse chemistries, have properties that meet our criteria.

Speaker Change: So what's really interesting about a ZETU calendar is there isn't any one specific attribute of a ZETU calendar which we're trying to improve on.

Sherry Aulin: Thank you all today for your attention and we look forward to sharing more in the coming months.

Unknown Attendee: I'll now ask the operator to open the line for any questions. Thank you. The floor is now open for questions. If you have dialed in and would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again.

Speaker Change: Right now, as we've gone through the data, as we've mentioned.

Speaker Change: You know, this is best in category efficacy on a placebo-adjusted basis, the novel mechanism, the rapidity of onset.

Speaker Change: So we think we have so many of the important attributes to be successful both in epilepsy and depression that these next generation molecules have diverse chemistries, have properties that meet our criteria, but we're not specifically trying to improve on any one attribute from a Z2 calendar.

Ian Mortimer: But we're not specifically trying to improve on any one attribute of azethutaliner. There will be an opportunity, as you mentioned, to have some therapeutic diversification. So as we move forward, you know, obviously, for this mechanism, we continue to be excited about epilepsy, neuropsychiatry, pain, and other indications. So absolutely, you'll see the next molecules go into some indications that we're not going to with azethutaliner.

Unknown Attendee: If you're called upon to ask your question and are visiting via loudspeaker on your device, please pick up your handstand and ensure that your phone is not on mute when asking your question.

Speaker Change: There will be an opportunity, as you mentioned, to have some therapeutic diversification. So, as we move forward, you know, obviously, for this mechanism, we continue to be excited about epilepsy, neuropsychiatry, pain, and other indications. So, absolutely, you'll see the next molecules go into some indications that we're not going to with a Z2 calendar as well.

Paul Maseus: And your first question comes from the line of Paul Maseus with Stivel. Please go ahead. Hey there, good afternoon, congrats from all the progress. As it relates to XO2, I was wondering if by now you have a good sense of how the patient demographics as it relates to baseline future frequency, refractoriness, et cetera, comparing to XO1. And then just as it relates to your updated timing guidance for top line, thanks for that is the expectations still that you'll complete enrollment around the end of this year early next year.

Paul Maseus: Thank you so much. Thanks, Paul. I'll take the second one, and maybe make a quick comment on the first one, Chris Kenney, if you want to add any of your perspective as well. So on the first question, just on demographics. So obviously we track that. We see it on a blinded basis, and all the things we'd expect us to track. We're looking at on a blinded basis. You know, we haven't historically given any information publicly on what we're seeing just because as the study's ongoing, those demographic data are changing all the time.

Unknown Speaker: Got it. Thank you so much.

Speaker Change: Got it. Thank you so much. I guess a quick follow-up to that. You highlighted some

Unknown Speaker: And I guess a quick follow-up to that. You highlighted some additional, you know, neuropsych indications. Will you be looking at data from KV7 competitor in bipolar mania and potentially migraine to kind of inform the indications you plan to assess with this next-gen molecule? Might be a little bit too mature of a question to ask. Thank you.

Speaker Change: Editional, you know, North Psych Indication.

Speaker Change: Will you be looking at data from KV7 competitor in bipolar mania and potentially migraine to kind of inform the indications you plan to assess with this next-gen molecule? Might be a little bit too mature of a question to ask. Thank you.

Ian Mortimer: Yeah, and Chris Kenney and Chris Lonsager, feel free to add your perspective here. I'll start, and if you want, please add to it. Yeah, we've done a significant amount of LCM work on the mechanism. You know, we're very much informed by what we learn and the work that we do rather than anchoring to any competitive product. And we're making decisions all the time.

Speaker Change: Yeah, and Chris Kenney, Christopher Seggern, feel free to add your perspective here. I'll start and please add to it. Yeah, we've done a significant amount of LCM work on the mechanism. You know, we're very much informed by what we learn.

Speaker Change: and the work that we do rather than strengthen anchoring to any competitive product, and we're making decisions all the time and, you know,

Paul Maseus: So, but we are we're definitely tracking it. So as we get to the end of patient screening and randomization, we can we be in a position to give some of that information publicly, but Chris Kanad in a minute there also. Yeah. And then in terms of guidance, I think you've kind of nailed it. We've moved to top line day of guidance now. So just to reiterate, I know we said it a few times, but X told to top line guidance, second half of next year, you know, just to take a step back, I think we said it before it's about six to eight months from last patient screened to top line data.

Speaker Change: You know, the the KV drug that you're probably referring to in development is years and years and years away from any efficacy data and we'll be making decisions.

Chris Kenney: And, you know, the KV drug that you're probably referring to in development is years and years and years away from any efficacy data, and we'll be making decisions far in advance of that. So, you know, we'll make decisions based on all of the work that we've done where we think these molecules would be best suited for early clinical development. But we've done, you know, probably over the last year or more, we've done a lot of work to do commercial assessments and mechanistic assessments and a bunch of preclinical work to understand best where we can take these molecules in the future.

Chris Kenney: Farm Advance of that. So, you know, we'll make decisions based on all of the work that we've done where we think these molecules would be best suited for early clinical development. But we've done, you know, probably over the last year or more, we've done a lot of work to do commercial assessments and mechanistic assessments and a bunch of free clinical work to understand best where we can take these molecules in the future. But Chris, or Chris anything to add to that.

Paul Maseus: And that's because these patients go through a screening period. And then there's a two months baseline period where they have to count seizures and an electronic diary that we can come up with a monthly seizure burden. Then the randomization visit happens. And there's three months of the double blind period. And then there is safety follow up that safety follow up, the timing depends a little bit on whether those last patients go into open label extension or not.

Chris Kenney: I'll just say something quick. You know, in his prepared remarks, Ian talks about KB7 offering the potential for a pipeline and a mechanism opportunity.

Chris von Seggern: But Chris or Chris, anything to add to that?

Speaker Change: and his Chris von Seggern and I and our teams have looked at life cycle management. There are a lot of different options. This is a mechanism that really should work in all types of epilepsy, which is what gave us the confidence to go into focal length at seizures in primary, generalized tonic, chronic seizures in parallel.

Paul Maseus: So, you know, just kind of back all that out, you know, where exactly screening will complete. You know, we're comfortable with our guidance, the second half data, which means that you kind of back out six to eight months from that is when we expect patients screening to be completed. So hopefully that just gives a little bit more background and color on kind of the process that we're going through on Chris anything else on the demographics that you want to comment on.

Chris Kenney: I'll just say something quick. You know, in his prepared remarks, Ian talks about KB7 offering the potential for a pipeline and a mechanism opportunity. And as Chris von Segern and I and our teams have looked at lifecycle management, there are a lot of different options. This is a mechanism that really should work in all types of epilepsy, which is what gave us the confidence to go into focal onset seizures and primary generalized tonic-clonic seizures in parallel.

Chris Kenney: There are a number of psychiatric indications of interest. I think we would probably put bipolar to top of that list, but there are several others of interest and then pain. So I think it's an interesting target and we have lots of different options with these backup compounds. Chris?

Chris von Seggern: Yeah, thanks, Chris. I think the only thing that I can add here is just reiterating that the extensive work that's been done, both from a commercial perspective, gathering input from potential prescribers in the future, as well as on the scientific side, where we where we've looked in depth at level of genetic validation and now emerging clinical validation, based on the backbone of these at the calendar profile, really just creates a range of potential options that we're incredibly enthusiastic about, in part, driving the decision for us to advance multiple products into the clinic.

Chris Kenney: There are a number of psychiatric indications of interest. I think we would probably put bipolar at the top of that list, but there are several others of interest, and then pain. So I think, you know, it's an interesting target, and we have lots of different options with these backup compounds. Chris? Yeah, thanks, Chris.

Paul Maseus: Yeah, so just as a reminder, the seizure burden in the X pole phase 2B study was pretty high. Patients had an average of 13 and a half seizures per month at baseline, half the population were taking three anti seizure medications. And on average patients had failed six anti seizure medications even before coming into the study. And despite that, we saw really robust efficacy with the largest separation between the high dose and placebo.

Chris Kenney: Yeah, thanks, Chris. I think the only thing that I can add here is just reiterating that the extent of work that's been done, both from a commercial perspective, gathering input from potential prescribers in the future, as well as on the scientific side, where we've looked in depth at level of genetic validation and now emerging clinical validation, based on the backbone of these at the calendar profile, really just creates a range of potential options that we're incredibly enthusiastic about. In part.

Paul Maseus: And from the perspective of median percent change in seizure frequency compared to any other study we can find and focal on seizures. So we're pretty pleased with that. So the spirit of the subsequent phase 3 program is do the best you can to not deviate from what was done in X pole because that worked out pretty well. And so that's what we've tried to do. And more directly as an answer to the question, what we're seeing is so far is that the population has shaped up very similarly in the phase 3 program as it did in the phase 2 study.

Chris Kenney: driving the decision for us to advance multiple products into the clinic.

Unknown Speaker: Thank you so much. Again, if you would like to ask a question, press star one on your telephone keypad. Your next question comes from the line of Brian Skorney with Baird. Please go.

Operator: Again, if you would like to ask a question, press star 1 on your telephone keypad. Your next question comes from the line of Brian Skorney with Baird. Please go ahead.

Speaker Change: Again, if you would like to ask a question, press star 1 on your telephone keypad. Your next question comes from the line of Brian Skorney with Baird. Please go ahead.

Chris Kenney: Hi, this is Luke on for Brian. Thanks for taking the question.

Luke: On NAV 1.7, can you talk about your biggest learnings from legacy challenges with the mechanism in the past?

Paul Maseus: And obviously we're keeping an eye on that in real time gives the opportunity to make an adjustment if you had to, if you were getting something unexpected, but we're not right now. Keep it here. All right. Thank you both very much.

Speaker Change: And then apologies if this is something you've discussed before but can you remind us whether you intend to conduct non-human primate studies, to get a better idea of the profile before entering the clinic, given it seems there's been challenges with translation utilizing rodent models in the pal.

Brian Abrahams: Your next question comes from the line of Brian Abrahams with RBC Capital Markets. Please go ahead. It's a little one for Brian. Thanks for taking my question. I had maybe one and then just a quick clarifying question as well. I guess on the MDD trial design. I guess as you're thinking about how to counter my position itself and there's a number of other agents that are also potentially having effects on Anatonia.

Operator: Uh, sure, Luke. Yeah, you and when you're talking about non-human primate models, you're talking specifically about NAB 1.7. Yeah, yeah. Okay, sure. Yeah, I can take this.

Speaker Change: Session.

Luke: Sure, Luke. Yeah, you're and when you're talking about non-human primate models, you're talking specifically with NAB 1.7.

Ian Mortimer: And then others can add. Yeah, so I think what you're referring to is that, you know, NAV1.7, or the gene, which is SCN9A, was sequenced quite some time ago. And there have been a number of companies, us included, that have tried to prosecute against the target. And we just haven't made it into late stage clinical development for a number of reasons. There's not just one reason.

Speaker Change: Yeah, yeah.

Speaker Change: Okay, sure. Yeah, I can take this. And then others can add. Yeah, so I think what you're referring to is that, you know,

Brian Abrahams: I guess as those other competitive trials and I think of the Capitol bill, it starts to read out. I guess are you looking for any data there and how they perform on Anatonia to maybe inform and whether you want to change selection for Anatonia or you know how that might impact market positioning for the calendar and then just to clarify. I think you guys said that you're not running XUS sites for the MDD phase three program.

Speaker Change: Now 1.7 or the or the gene which is SCN 9a was was

Speaker Change: sequence quite some time ago and there's been a number of companies

Speaker Change: us included that have tried.

Speaker Change: to prosecute against the target and we just haven't made it into a late stage clinical development. Here's kind of a number of reasons. There's not one reason. I think a lot of the drugs that other companies are called.

Ian Mortimer: I think a lot of the drugs that other companies called selective 1.7 inhibitors were not actually selective. They were much more pan-sodium channel inhibitors. And so I think selectivity matters.

Speaker Change: Selective one seven inhibitors, we're not actually selectives, there were much more pan sodium channel inhibitors

Brian Abrahams: And I think maybe before you hit so that you would use both international and US sites. I guess can you maybe talk about what drove that change if I heard you guys correctly and maybe the how that might impact many expectations on on timing and how quickly you can move. Thanks. Thanks Leo. I can start and then Chris Kenny to add in on the MDD side and Chris one second. If you can provide perspective a little bit about the market and will we're hearing back in our market research and the importance of of an adonia and maybe how we believe.

Ian Mortimer: And we've made, you know, really great progress on the selectivity profile and therapeutic index and selectivity across the other isoforms. There were definitely some toxicity issues related to certain chemistries on the target historically, and so I think we've learned a lot there. And then, excuse me, I would say the last thing is around the pharmaceutical properties.

Speaker Change: and so I think selectivity matters and we've made really great progress on a selectivity profile and therapeutic index and selectivity across the other ice of forms.

Speaker Change: There were definitely some toxicity issues related to certain chemistries.

Speaker Change: on the target historically, and so I think we learned a lot there.

Speaker Change: and then doesn't want to see me, I would say.

Ian Mortimer: I think we've learned a lot about the expression patterns and distribution and really where we need to get these molecules to be successful. So I think we've learned a ton from the field and our own work that we've done over the past 15 years or so internally, where we have molecules that meet all of our criteria that we're really excited to run the human clinical experiment. In terms of translatability, translatability is hard for this target because the human NAV1-7 is different than in other animal species.

Speaker Change: The last thing is around the pharmaceutical properties.

Brian Abrahams: Is that to counter can differentiate with with some of the other molecules, both in development, but also those that are commercially available currently. So a couple of comments yeah just on clarification in terms of the XUS US sites. We've said that you know we're running three phase three clinical trials and depression. We we had always this isn't a change we always expected the definitely the first study which will start in the next couple of months.

Speaker Change: I think we've learned a lot about the expression patterns and distribution and really where we need to get these molecules to be successful.

Speaker Change: I think we've learned a ton from the fields and our own work that we've done over the past 15 years or so internally where we have molecules that meet all of our criteria that were really excited to run the human clinical experiment.

Speaker Change: In terms of translability, translability is hard for this target, because the human level 7 is different than in other animal species.

Brian Abrahams: Would focus on US sites as we get to the second and the third. Studies we may move to some XUS sites, but right now that's where the phase two is run. I think that's where a lot of the clinical development for major depressive disorder is done in the US. So we'll definitely focus that for act will we're calling X Nova to which is the first phase three. And then as we move into the other phase three there may be some difference in site selection as we move forward.

Ian Mortimer: We do use some genetic models and human knock-in models to help us with that, but really, I think we need to run the human experiment. What we can do in animals is really understand the therapeutic index and ensure that we have, you know, we run the appropriate tox species from a regulatory point of view.

Speaker Change: We do use some genetic models and human knock-in models to help us with that, but really I think we need to run the human experiment. What we can do in animals is really understand the therapeutic index.

Speaker Change: and sure that we have, you know, we run the appropriate talk species from a regulator point of view. But we really need to run the human experimental experiment to be able to answer that question. The nice thing is you know about pain is there's an opportunity to run this earlier in human clinical development than proof of concept in some other therapeutic indications and the early studies run quite quickly as well. So, I think we've made tremendous progress on this target and I don't think we're actually far away from being able to run this human experiment.

Ian Mortimer: But we really need to run the human clinical experiment to be able to answer that question. The nice thing, as you know, about pain, is there's an opportunity to run this earlier in human clinical development than with proof of concept and some other therapeutic indications. And the early studies are running quite quickly as well. So I think we've made tremendous progress on this target. And I don't think we're actually far away from being able to run the human experiment.

Brian Abrahams: So hopefully that helps you know in terms of the protocol. You know how we may be informed by other readouts you know the protocol for us in the MDD study is locked so we as Chris said in his prepared remarks. We have we have filed the phase three protocol to the with the FDA we expect to hear back shortly on that and initiate that study so in terms of the inclusion exclusion criteria as it relates to baseline.

Brian Abrahams: Both depression and and Hodonia all of that stuff is now locked. And as we said on previous calls I think we're very much informed by our phase two program using MD 17 is primary and also increasing the severity of the patients as we move from phase two to phase three. So although I think you know additional readouts are always interesting. They're not going to change in terms of our strategy or approach.

Speaker Change: Awesome thanks!

Speaker Change: You're welcome.

Operator: Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead.

Unknown Speaker: Awesome. Thanks. You're welcome. Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead. Hey, good afternoon. Congratulations on the execution. Thanks for the update.

Speaker Change: Your next question comes from the line of Andrew Sawyer, Wake Jeffrey, please go ahead.

Speaker Change: Hey, good afternoon, congrats on the execution, thanks for the updates. One of the apps on PGTCS, this time could it be possible? We get data in 2025, or should we be assuming 2026 at the earliest? I think you guys have mentioned before how the study is powered to show what other drugs show within this indication. So, would it be fair to assume a 30 to 40% type placebo-aggressive separation and seizure reductions that could be the bar here? Thank you.

Brian Abrahams: But Chris can you what do you add to that and then Chris wants to go on just differentiation in the marketplace. Yeah, I would just just zooming out from an adonio for a second. I think why this. Why is it to tell her so interesting and MDD is really kind of a constellation of features not just an adonio so we've got the unique mechanism of action. We have the rapidity of onset which also happened in focal onset seizure patients which makes you think it's it may be real.

Ian Mortimer: Thanks, Andrew. I can, maybe, talk about timelines. Chris Kenney, do you want to talk about power and kind of the expectations for moving from FOS to PGTCS and some of the changes there in terms of what our expectations are? And maybe actually just the baseline seizure burden coming in as well? I think it would be helpful to put that into context. But Andrew, in terms of timeline, we haven't guided yet on XACT, which is our phase three clinical trial and primary generalized tonic-clonic seizures.

Chris Kenney: Thanks Andrew. I can maybe talk about timelines. Chris Kenney, do you want to talk about power and kind of the...

Chris Kenney: Expectations for moving from FLS to PGTCS and some of the changes there in terms of what our expectations are. And maybe actually just the...

Brian Abrahams: And then the safety so on the safety side from an MDD perspective we had, you know, no notable issues with sexual side effects or weight gain. And in fact the drug at 20 milligrams was better tolerated in the MDD population compared to the focal onset seizure population. So you know that safety tolerability data know SAEs and in any of the the 10 or 20 milligram treatment groups in ex Nova that is I think it's.

Chris Kenney: They find seizure burden coming in as well, I think would be helpful to put that in the context.

Chris Kenney: But Andrew, in terms of timelines, so we haven't guided you on exact, which is our phase 3 clinical trial in primary generalized tonic clonic seizures.

Ian Mortimer: I mean, if we look at the literature and the most recent studies that have been run, Sinovimate, they're still running their PGTCS study even though that drug is approved. If you look at lacosamide, where they had data very late in the commercial life of that product, you know, these are more challenging studies to run. They run much slower than the focal onset seizure studies. So although we haven't yet given guidance on it, I just want to set expectations that these studies are slower than what we would expect in the XTOL program, given PGTCS is less common and these studies take longer than focal onset seizures.

Speaker Change: I mean, if we look at the literature and the most recent studies that have been run, Sinobamate, they're still running their PGTCS study, even though that drug is approved. If you look at lacosamide, where they had data very late in the commercial life of that product.

Brian Abrahams: You know is is important to perhaps even more so but I would say it's more the constellation of all those features not one per se. And maybe I'll turn it to Chris to see if he what his perspective is from the commercial perspective. Yeah, thanks, Chris. So maybe just to ground everyone when we think about the major depressive disorder treatment landscape, it's important to note that on the main day of treatment in this space SSRI, SSNRIs, notably do not have a benefit, specifically on the antidote component of the disorder.

Chris Kenney: These are more challenging studies to run, they run much slower than the focal onset seizure studies.

Brian Abrahams: And when we conduct our market research, as we think ahead towards commercializing a septic calendar in major depressive disorder, clinicians have very clearly identified anodonia as one of those constellation of features that Chris Kenney mentioned, but also the fact that having a benefit in this core symptom domain or comorbidity of major depressive disorder is something that is very, very encouraging. And clinicians are actively looking for, given the fact that the SSRIs and SNRIs don't provide benefit along that to mention.

Chris Kenney: So, although we haven't yet given guidance on it, I just want to set expectations that these...

Chris Kenney: Studies are slower than what we would expect in the XTOL program, given PGTCS is less common and these studies take longer than the focal onset seizures.

Chris Kenney: And at the appropriate time, we'll be able to update in terms of guidance to top-line data. But Chris, maybe you can just give, because we didn't in today's prepared remarks, a little bit of background on the steady design and the powering assumptions.

Chris Kenney: And at the appropriate time, we'll be able to update you on guidance to top line data. But Chris, maybe you can just give, because we didn't in today's prepared remarks, a little bit of background on the FETI design and the powering assignment. Yeah, sure. Thanks, Ian. I mean, one of the things there are, you know, there are

Chris Kenney: I mean, one of the, you know, there are a few differences going from focal onset seizures to primary generalized tonic-clonic seizures. One is that the PGTCS population, in general, has a lower seizure burden, and it's difficult to find those patients. And so that's why you end up seeing the duration of the study take a little bit longer. But fortunately, when the drugs work, they work really well, and you need fewer patients to show efficacy.

Chris Kenney: Yeah, sure. Thanks, Ian.

Chris Kenney: Yeah, sure. Thanks, Ian. I mean, one of the, you know, there are a few differences going from focal onset seizures to primary generalized tonic-clonic seizures.

Chris Kenney: One is that the PGTCS population in general has a lower seizure burden, and it's difficult to find those patients. And so that's why you end up seeing the duration of the study take a little bit longer. Now fortunately, when the drugs work, they work really well, and you need fewer patients to show efficacy.

Brian Abrahams: So when we do our research and we do our testing of a potential as a septic calendar profile, it's something that clinicians absolutely latch on to and appreciating that folks are now focused on this area in large part because of the unmet medical need that exists in the marketplace today. Thanks, Chris.

Chris Kenney: So as you look at the spectrum of what's been done in the past, on the low end, you have the study that was done with tapiramate that just had about 40 patients per group, so 40 times 2. And I think it was lamotrigine that had 60 patients per arm, so 60 times 2 for the total size. And then there are three examples of studies, PGTCS studies, that had about 80 patients per arm, so a total of about 160 patients.

Chris Kenney: So as you look at the spectrum of what's been done in the past, on the low end, the study that was done, it's a pyramid just had about 40 patients.

Unknown Attendee: Operator, we can move to the next question. Again, if you would like to ask a question, press star one on your telephone key bag.

Speaker Change: for 2-beet-o.

Speaker Change: per group, so 40 times 2. And I think Lamotrigine had 60 patients per arm, so 60 times 2 for the total size. And then there are three examples of studies, PGTCS studies, that had about 80 patients per arm, so a total of about 160 patients.

Tesla Romero: Very next question comes from the line of Tesla Romero with JP Morgan. Please go ahead. Good afternoon. Thank you for taking our question. So Ian, you've outlined top line X2 data in the second half of 2025 here. Thinking back up on like an earlier question that was asked, maybe asked slightly differently. Can you just provide a little bit of an updated view for us on how the pace of enrollment has been going?

Chris Kenney: Two examples include parampanil and levatorazotam, and that's what we've anchored to, sort of on the higher end of that spectrum of between 40 to 80 patients. I mean, the one exception that included even higher numbers of patients was the leucosomide study, but that was a time-to-event study with a different entry criteria, so it's sort of comparing apples to oranges. But so we're on the higher end of that, and, you know, we don't, I mean, compared to focal onset seizures, we don't have preliminary data. And so our study was simply powered over, you know, compared to those three examples of previous studies that used about 80 patients per arm. Thanks.

Speaker Change: Parampanil, Levitirazotam, and that's what we've anchored to sort of on the higher end of that spectrum of between 40 to 80 patients.

Speaker Change: The one exception that included even higher patients was the glucosamide study, but that was a time-to-event study with a different entry criteria, so it's sort of comparing apples to oranges.

Speaker Change: But so we're on the higher end of that and we don't, I mean, compared to focalons, it's users we don't have preliminary data and so our study was simply powered over, you know, compared to those three examples of previous studies that used about 80 patients grown.

Tesla Romero: And you know, just kind of curious, has it been pretty steady since all the sites were activated? Or are there, have you observed any changes due to competitive dynamics or anything else here in the US or globally across sites? And can you just remind us what the split is between US and XUS sites and what are the key regions outside the US? Thanks so much. Thanks, yes. Yeah, I think I've got it all, but others can jump in if I've missed something.

Speaker Change: [inaudible]

Speaker Change: Thanks.

Speaker Change: Thank you for watching, and I'll see you in the next video, and I'll see you in the next video.

Operator: Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead. Excuse me, Mr. Choi, we cannot hear you. Can we check your line, please? Thank you.

Speaker Change: Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead.

Tesla Romero: So yeah, in terms of, you know, pace of enrollment and kind of top line guidance, as you said, top line for X2, second half 25. I think it's really exciting for us, right? I mean, that's a critical path now. We, we, with the data from X2, with X2, will be ready to engage with FDA and file an NDA. So that's, it's really exciting now to have that top line data guidance out in terms of cadence or pace of enrollment.

Speaker Change: [inaudible]

Speaker Change: Thank you very much for watching this video.

Speaker Change: Please see the complete disclaimer at https://sites.google.com

Speaker Change: Excuse me, Mr. Troy, we cannot hear you, kind of we check your line please, thank you.

Operator: Operator, we can move to the next question and then we can go back to... Oh, hi. Sorry. Can you hear me? Oh, hey Paul, yeah, we can hear you now. Sorry, sorry about that. I just wanted to ask a follow-up question on NAV 1.7 with regard to development and pain. And can you comment, you know, pending, pending the animal model?

Speaker Change: Operator, we can move to the next question and then we can come. Alright, can you hear me?

Operator: Oh, hey, Paul. Yep, we can hear you now. Sorry about that. I just wanted to ask a follow-up question about...

Tesla Romero: You know, we said on previous calls that just the number of sites that you need to complete these studies, which is kind of in, you know, 100 medical centers give or take in each of X2 and X2 free is that you just naturally do get some ebb and flow and up and down of enrollment. So we've been comfortable with where we are and we're comfortable with the guidance that we're giving. And, you know, obviously we have more experience in running these types of studies than anybody else out there right now.

Speaker Change: Sorry about that. I just wanted to ask a follow-up on NAV 1.7 with regard to development and pain.

Speaker Change: And can you comment, you know, pending the animal model work, what you see as the most...

Speaker Change: Logical Development focuss for that area. Would you focus on acute development clinical strategy or a focusing perhaps on the larger chronic opportunity for us or prosecute them in parallel? Thanks, Ian.

Tesla Romero: So I think we're in really good shape. You know, in terms of competitive pressures, we haven't seen anything. So we haven't seen the pace of enrollment change from a competitive perspective where, you know, obviously, you know, when we were running X2, there's at times other studies that are being run and the same thing when you're running, when we're running X2. And that's not just all, you know, I think your question's probably a little bit more focused on drug trials, but there's device studies as well that are ongoing.

Ian Mortimer: Yeah, Paul, I think it's a really good question. I would say it's probably a bit premature for us to, we haven't fully fleshed out what kind of a late stage clinical development plan would look like. Obviously, we would do healthy volunteer work initially, make sure that we believe we're getting appropriate exposure, where we can do some modeling and predictability to see if we have enough receptor occupancy from an efficacy point of view. So that would be the early work.

Speaker Change: Yeah, Paul, I think it's a really good question. I would say it's probably a bit premature for us to, we haven't fully fleshed out what kind of a late stage clinical development plan would look like. Obviously, we would do healthy volunteer work initially, make sure that we believe we're getting appropriate exposure, where we can do some modeling and predictability that we have enough receptor occupancy from an efficacy point of view. So that would be the early work. And then as I was mentioning earlier, the nice thing about pain is we would likely run a bunionectomy study, right? And those studies can be run very quickly at reasonable size in terms of powering as well. We haven't designed a study like that yet. So there's a whole bunch of questions there in terms of number of active doses and potentially active controls and other things, and we'll get to it.

Ian Mortimer: And then, as I was mentioning earlier, the nice thing about pain is that we would likely run a bunionectomy study, right? And those studies can be run very quickly, at a reasonable size, in terms of powering as well. We haven't designed a study like that yet, so there are a whole bunch of questions there in terms of the number of active doses and potentially active controls and other things. And we'll get to all of that in advance.

Tesla Romero: So there's always other things that are happening often at these clinical centers. But we haven't really seen any change in the last little while that has given us any pause or any concern. In terms of regions, so X2, we've really tried to use X2 as much of our guides. We went back to a lot of the same centers from X2 and X2 and used investigators that have experience with the molecule. As a reminder, in the X2 phase 2 study, we had sites, clinical sites in Europe and clinical sites in the US.

Speaker Change: all of that in advance.

Speaker Change: But you're really asking a question more about kind of the acute and chronic longer-term studies Which you know, I think are both on the table at least based on the mechanism There's nothing to suggest with the genetics or the mechanism that we should necessarily lean one way or another

Ian Mortimer: But you're really asking a question more about kind of the acute and chronic, longer-term studies, which, you know, I think are both on the table, at least based on the mechanism. There's nothing to suggest with the genetics or the mechanism that we should necessarily lean one way or another. But, but so I would say today's both, both are potentially on the table; we do want to really monitor how the NAV1A program is doing, and how they're doing in terms of accessing the commercial market, in terms of the acute market, to start.

Speaker Change: but so I would say today's both are potentially on the table. We do want to really monitor how the Nav1A program is doing and how they're doing in terms of accessing the commercial market and in terms of the acute market to start. So I think that's going to be an interesting

Tesla Romero: At the end of the day, 60% of patient enrollment came from Europe and 40% came from the US. Again, you know, while we're partly through a study, I don't really want to comment on where we're coming from in X2, but the same jurisdictions that we used in X2 were using in X2 too. I think I got all of your questions there, but if there's anything else, Thank you. You did. Thanks so much Ian. Talk to you soon. Thank you so much.

Speaker Change: You know, data point for two and four months as well. So I don't have a really good, you know, definitive answer for you today because I think it's just too early and too premature. But more to come on that over the next year or two. Thank you.

Ian Mortimer: So I think that's going to be an interesting data point for us to inform us as well. So I don't have a really good, you know, definitive answer for you today because I think it's just too early and too premature, but more to come on that over the next year or two. Okay, Ian. Your next question comes from the line of Dean Bohnsack with T.D. Cohen.

Operator: Your next question comes from the line of Tim Bohnsack with T.D. Cohen. Please go ahead.

Unknown Attendee: Again, if you would like to ask a question, press star one on your telephone keypad.

Speaker Change: Good luck.

Speaker Change: Your next question comes from the line of Dean Bonsack with J.D. Cohen. Please go ahead.

Dina Ramadane: Your next question comes from the line of Jason Gerberry with Bank of America. Please go ahead. Hi, good afternoon. This is Dina on for Jason. Thank you so much for taking our question. Jason, we just wanted to ask about the next generation KD7 asset that's an I&D enabling studies. Could you please provide some more color on the specific drug properties that led you to advance this asset. Is your aim to improve upon as it's to cool Mars profile or is it is more of a life cycle management play to advance KD7 into neuropsych opportunities beyond the current, you know, epilepsy and MDD said.

Operator: Please go ahead. Hi guys, thanks for taking our questions. I guess could you talk a little bit more about the design of the

Dean Bonsack: Hi, guys. Thanks for taking our questions. I guess, did you talk a little bit more about the design of the MDED total program? I guess in terms of just initiating studies and enrollment and then the data releases, are you playing on staggering initiation on 1, 2, 3, or are you going to initiate them all at once?

Speaker Change: And then for the data releases, basically the same question, will it be released all at once or will it be done if the study analysis is completed? And then, just secondly and real quickly, apologies if I missed this, is MATRA still being measured in these studies?

Ian Mortimer: Yeah, I'll take the first part on staggering. And then, Chris, Kenny, I think it's probably helpful, maybe just to go through some of the entry criteria into the study because, you know, we learned a lot from phase two as we're moving into the phase three program. I think we can kind of review some of that. We didn't have time to do that in the prepared remarks.

Speaker Change: Thank you. Yeah, I'll take the first part of on the staggering and then.

Chris Kenney: Chris Kenney, I think it's probably helpful maybe just to go through some of the entry criteria into the study because, you know, we learned a lot from phase two as we're moving into the phase three program. I think we can kind of review some of that. We didn't have time to do that.

Dina Ramadane: Thank you. Thanks, Dina. Yeah, I think it's a really important question. Obviously, the success we've had with is that you counter now in late stage clinical development. We think it's really important for us to continue to maintain and build upon what we think is really a considerable leadership position in this mechanism, which we're really excited about. So we've been working on additional molecules against the same target for quite some time. So completely diverse chemistries from from is that to tell her.

Speaker Change: In the prepared remarks, and then maybe you can address this as a question on Madras.

Ian Mortimer: And then maybe you can address this as a question on Madras. So we're gonna we'll be staggering these studies. So just naturally, they won't start at all at the same time. So our first study, we filed the application, the protocol with FDA, and that should start later this year, as we've guided. And then we'd expect a natural stagger for the second and the third studies. And that would be our expectation for the release of data as well, that when the first study is complete, and we've unblinded those data, we'll provide those data publicly. And then the second study and the third study would follow suit after that. So expect a stagger.

Speaker Change: So we're gonna be staggering these studies, so just naturally they won't start at all at the same time.

Speaker Change: So our first study, we filed the protocol with FDA, and that should start...

Speaker Change: later this year, as we've guided. And then we'd expect a natural stagger for the second and the third studies. And that would be our expectation on the release of data as well, is that when the first study is complete, and we've

Dina Ramadane: As you mentioned, and we said in our prepare remarks, multiple candidates have been identified, including the lead one is in GLP toxicology studies. So we're excited to get that into human clinical development as well. You know, we touched upon what we call our DTC or development track candidate and you asked the question around drug properties. It's a quite a long list of things that we try to optimize all of these drugs for obviously potency and selectivity on target, but a bunch of the drug properties as well.

Chris Kenney: Unblinded those data will provide those data publicly, and then...

Speaker Change: The second study and the third study would follow suit after that. So expect a stagger, not from a perspective that we're waiting for a readout on the first one before we start the second one, but so at some point they will all be running.

Ian Mortimer: Not from the perspective that we're waiting for a readout on the first one before we start the second one. But so, at some point, they will all be running near about the same time, but we would definitely start the first one and finish that and unblind those data and provide them. But Chris, maybe you can go through some more of the entry criteria, because I think that's important for this program. And then answer the question about Madras. Sure. Thanks, Ian. Yeah, I would do that.

Chris Kenney: near about the same time, but we would definitely start the first one and finish that and unblind those data and provide them. But Chris, maybe you can go through some more of the entry criteria, because I think that's important for this program, and then answer the question around Madras.

Dina Ramadane: So what's really interesting about is that you counter is there isn't any one specific attribute of is that you counter which we're trying to improve on. Right now is we've gone through the data as we've mentioned, you know, this is best in category efficacy on a placebo adjusted basis, the novel mechanism, the rapidity of onset. So we think we have so many of the important attributes to be successful both in epilepsy and depression that the these next generation molecules have diverse chemistries have properties that meet our criteria.

Chris Kenney: Sure. Thanks, Ian. Yeah, I would say three things about the study design that should work in our favor. The first is that as we go from phase two to phase three, we'll just have one treatment group versus placebo. So, if you look at other studies, that definitely helps in terms of placebo response. The other thing is that the size of the study, you know, in the prepared remarks, we talked about a study size of 450 patients, so 225 per arm.

Chris Kenney: Sure, thanks Ian. Yeah, I would say three things about study design that should work in our favor. The first is that as we go from phase two to phase three.

Chris Kenney: We'll just have one treatment group versus placebo, so that, if you look at other studies, that definitely helps in terms of placebo response. The other thing is that the size of the study, you know, in the prepared remarks, we talked about a study size of 450 patients, so 225 per arm.

Dina Ramadane: But we're not specifically trying to improve on any one attribute from is that to counter there will be an opportunity as you mentioned to have some therapeutic diversification. So as we move forward, you know, obviously for this mechanism, we continue to be excited about epilepsy neuropsychiatry, pain and other indications. So absolutely, you'll see the next molecules go into some indications that we're not going to with is that to counter as well.

Chris Kenney: So that's, you know, three, four times higher than what was used in the phase two study, Ex Nova. And there were some imbalances, not dramatic, but subtle imbalances that occurred in the Ex Nova study. So that larger study design, you know, I think is guaranteed to iron those things out. And then, another thing more specifically directed to the question: we're still going after moderate to severe depression. What we learned mirrors what other studies have learned, which is that if you have patients that slip in with those that are slightly on the milder end of the spectrum, even though they meet the criteria for being moderate to severe, but if they're on the milder end of the spectrum, then they can skew the data a bit.

Dina Ramadane: Got it. Thank you so much. I guess a quick follow up to that you highlighted some additional, you know, neuropsych indications will be looking at data from KV7 competitor in bipolar media and potentially migraines to kind of inform the indications you plan to assess with this next gen molecule. Might be a little bit too mature of a question that Thank you. Yeah, and Chris Kenney, Chris Seggern, feel free to add your perspective here.

Chris Kenney: So that's, you know, three, four fold higher than what was used in the face.

Chris Kenney: Two study, Exnova, and there were some imbalances, not dramatic, but subtle imbalances that occurred in the Exnova study, so that larger study designed.

Chris Kenney: I think it's guaranteed to iron those things out.

Chris Kenney: And then the other thing more specifically directed to the question, we're still going after moderate to severe depression.

Chris Kenney: What we learned mirrors what other studies have learned, which is that if you have patients that slip in that are slightly on the more milder end of the spectrum, even though they meet the criteria for being moderate to severe, but if they're on the milder end of the spectrum, then

Chris Kenney: They can skew the data a bit and so we're just going to be more strict

Chris Kenney: And so we're just going to be more strict. In terms of the cutoff that we use for the HAM-D, and then there are some other criteria that we're, just in general, going to be more strict about making sure that nobody comes into the study on the milder end of the spectrum. Those are the big changes.

Chris Kenney: in terms of the cutoff that we use for the HAMD and then there are some other criteria that we're just in general going to be more strict about making sure that nobody comes in the study on the milder end of the spectrum. Those are the big changes.

Dina Ramadane: I'll start and if please add to it. Yeah, we've done a significant amount of LCM work on the mechanism. You know, we're very much informed by what we learn. And the work that we do rather than anchoring to any competitive product and we're making decisions all the time. And, you know, the KV drug that you're probably referring to in development is years and years and years away from any efficacy data and we'll be making decisions far in advance of that.

Operator: In terms of the modrus, one of the guiding principles in depression is to keep it as simple as you can, and that worked well with ExNova. We did actually use two scales, as you know, which is fortunate because it allowed us to choose the HAM-D to go into phase three. But we went back and forth about whether modrus should be included and ultimately decided not to, that, you know, assessing depression to the least amount that still led to a successful outcome was the best approach. So we're going to focus on HAM-D, which we saw in our study had dramatically less variability, and we've seen the same in other studies, and that's what we're focused on.

Speaker Change: In terms of the madras, I mean...

Chris Kenney: One of the guiding principles in depression is keep it as simple as you can.

Chris Kenney: and that worked well with Exnova.

Chris Kenney: I mean, we did actually use two scales, as you know, which is fortunate, because it allowed us to choose the HAM-D to go into phase three, but we went back and forth about whether modules should be included, and ultimately decided not that, you know, assessing depression to, you know, to the least amount that still led to a successful outcome was the best approach. So we're going to focus on HAM-D, which we saw in our study had dramatically less variability, and we've seen the same in other studies, and that's what we're focused on.

Dina Ramadane: So, you know, we'll make decisions based on all of the work that we've done where we think these molecules would be best suited for early clinical development. But we've done, you know, probably over the last year or more, we've done a lot of work to do commercial assessments and mechanistic assessments and a bunch of free clinical work. To understand best where we can take these molecules in the future, but Chris or Chris anything to add to that.

Chris Kenney: [inaudible]

Operator: Your next question comes from the line of Laura Chico with Webb Bush Securities. Please go ahead. Hi, can you hear me?

Speaker Change: Great, thank you very much.

Dina Ramadane: I'll just say something quick. You know, Ian is prepared remarks Ian talks about KV7 offering the potential for a pipeline and a mechanism opportunity. And as Chris once again and I and our teams have looked at life cycle management, there are a lot of different options. This is a mechanism that really should work in all types of epilepsy, which is what gave us the confidence to go into focal points at seizures and primary generalized tonnoconic seizures in parallel.

Speaker Change: Your next question comes from the line of Laura Chico with webbush ofurities, please go ahead.

Operator: Yes, we can hear you. Yes. Thank you very much for taking my question. This is Dylan on behalf of Laura Chico, and I'm not sure if this is a question for Chris, Kenny, or Ian, but we noticed within the SCN8A program partnered with Neurocrin, you're also looking at an X-ray candidate that's NAV1.2 or NAV1.6 inhibitor for focal epilepsy, and we were wondering if you see positive outcomes with N Would this also have read through to the broader seizure-related indications?

Laura Chico: Hi, can you hear me?

Ian Mortimer: Yeah, I can take that, Dylan. Yeah, there's a little bit of history here, which is probably helpful in going through it. So 3-5-2 is the molecule that, so these are sodium channel inhibitors that came out of Xenon's laboratories and were licensed as part of a transaction with Neurocrin, and Neurocrin is doing the development and paying for the development. So it's a milestone and royalty transaction for Xenon. So 3-5-2 is in the SCN8A Phase 2 clinical trial, as you mentioned right now.

Speaker Change: Yes, we can hear you.

Speaker Change: Thank you very much for taking my question. This is Dylan on for Laura Chico.

Speaker Change: And I'm not sure if this is a question for Chris, Kenny, or Ian.

Speaker Change: But we noticed within the SCN 8A program partnered with NuroKren.

Dina Ramadane: There are a number of psychiatric indications of interest. I think we would probably put bipolar at the top of that list, but there are several others of interest and then pain. So I think, you know, it's an interesting target and we have lots of different options with these backup compounds. Chris. Thanks Chris. I think the only thing that I can add here is just reiterating that the extensive work that's been done both from a commercial perspective gathering input from potential prescribers in the future as well as on the scientific side where we where we've looked in depth at level of genetic validation and now emerging clinical validation.

Speaker Change: You're also looking at a next lead candidate that's snap over to your navel point six

Speaker Change: Inhibitor for Focal Epilepsy, and we were wondering if you see...

Speaker Change: Positive Outcomes with

Chris Kenney: Yeah, I can take that Dylan. Yeah, there's a little bit of history here, which is probably

Speaker Change: Healthful in worse and going through. So 352 is the molecule that, so these are...

Speaker Change: Sodium channel inhibitors that came out of Xenon's laboratories and were licensed as part of a transaction with Neurocrin and Neurocrin is doing the development and paying for the development.

Dina Ramadane: Based on the backbone of these that to counter profile really just creates a range of potential options that were incredibly enthusiastic about in part driving the decision for us to advance multiple products into the clinic. Thank you so much.

Ian Mortimer: They did run that in a focal onset seizure study. That was a small proof of concept study of around 100 subjects that read out last fall, and they're not moving 3-5-2 forward in focal onset seizures. The molecule that we referred to today in the prepared remarks has a little bit of a different profile. So although it's highly potent on NAV1.6, it's also potent on another sodium channel called NAV1.2, whereas 3-5-2 was much more selective for 1-6.

Speaker Change: So it's a milestone and royalty transaction for Xenon. So 352 is in the SCN8A Phase 2 clinical trials you mentioned right now. They did run that in a focal onset seizure study. That was a small proof of concept study around 100 subjects.

Speaker Change: that read out last fall, and they're not moving 3, 5, 2 forward in focal onset seizures.

Unknown Attendee: Again, if you would like to ask a question, press star one on your telephone keypad.

Ian Mortimer: So we would consider this a dual inhibitor that has potency on both channels. Both channels are involved in excitation in the brain, so they are both well-validated targets. This next molecule is still preclinical, and as it goes into clinical development, Neurocrin, at that point, would guide in terms of what types of studies it would go into, but it would be into epilepsy studies as well. Is that background helpful? Yes, thank you so much for sharing the questions.

Luke Herrmann: Your next question comes from the line of Brian's corny with beard, please go ahead. Hi, this is Luke on for Brian. Thanks for taking the question. And on that one point seven, can you talk about your your biggest learnings from legacy challenges with the mechanism in the past. And then apologies if this is something you've discussed before, but can you remind us whether you intend to conduct non human primate studies to get a better idea of the profile before entering the clinic given it seems there's been challenges with translation utilizing rodent models in the past.

Speaker Change: The molecule that we referred to today on the prepared remarks has a little bit of a different profile So although it's highly potent on Nav1.6, it's also potent on another sodium channel called Nav1.2

Speaker Change: 3.5.2 was much more selective for 1.6, so we would consider this a dual inhibitor that has potency on both channels. Both channels are involved in excitation in the brain, so both well-validated targets.

Speaker Change: This next molecule is still pre-clinical, and as it goes into clinical development, Neurocrine at that point would guide in terms of what types of studies it would go into, but it would be into epilepsy studies as well. Is that background helpful?

Luke Herrmann: Thanks. Sure Luke, yeah, you're in when you're talking about non human primate models, you're talking specifically with now 1.7. Yeah, yeah. Okay, sure, yeah, I can take this and then others can add. Yeah, so I think what you're referring to is that, you know, now 1.7 or the or the gene, which is SCN 9A was was sequence quite some time ago, and there's been a number of companies us included that have tried to prosecute against the target and we just haven't made it into a late stage clinical development.

Speaker Change: Yes, thank you so much for taking the question.

Speaker Change: Yep, no problem.

Operator: Yep, no problem. Your next question comes from the line of Mark Goodman with Leering Partners. Please go ahead. Hi, this is Basma on 4Mark. We have a question about XACT.

Operator: Your next question comes from the line of Mark Goodman with Lyrinc Partners. Please go ahead.

Speaker Change: Your next question comes from the line of Mark Goodman with leering partners, please go ahead.

Basma: Hi, this is Basma on 4Mark. We have a question on XACT. Could you please remind us what we should expect in terms of the efficacy of Zine 1101 in the primary generalized seizures?

Luke Herrmann: Here's kind of a number of reasons. There's not one reason. I think a lot of the drugs that other companies called selective 1.7 inhibitors were not actually selective. There were much more pan sodium channel inhibitors, and so I think selectivity matters and we've made, you know, really great progress on a selectivity profile and therapeutic index and selectivity across the other isoforms. There were definitely some toxicity issues related to certain chemistries on the target historically, and so I think we've learned a lot there.

Speaker Change: Should we expect an efficacy in linus, what we've seen in the focal onset seizures? We also have a question about the dose, the 25 milligram. What kind of work you've done to actually feel comfortable about the use of this dose and this indication and whether you believe this dose will be efficacious or not?

Chris Kenney: Great, thanks for the question. Chris Kenny, over to you. Yeah, thanks. Thanks for the question.

Speaker Change: Thank you.

Speaker Change: Great, thanks for the question, Chris Kenney, over to you.

Chris Kenney: Yeah, thanks. Thanks for the question. So, as I sort of said earlier, one of the differences between the focal onset seizure population and the primary generalized population is that we don't have preliminary data. And so we powered the exact study based upon a few different examples of studies that were successful with other anti-seizure medications, and we took on the higher end of the number of patients just to be cautious. I mean, in general, the drugs that do work in primary generalized tonic-clonic seizures when they're effective, they're pretty darn effective.

Chris Kenney: Thanks for the question. As I sort of said earlier, we, one of the differences between the focalons that seizure population and the primary generalizes that we don't have preliminary data. So we power the exact study based upon a few different examples.

Luke Herrmann: And then, excuse me, I would say the last thing is around the pharmaceutical properties. I think we've learned a lot about the expression patterns and distribution and really where we need to get these molecules to be successful. So I think we've learned a ton from the field and our homework that we've done over the past 15 years or so. So internally where, you know, we have molecules that meet all of our criteria that we're really excited to run the human clinical experiment.

Speaker Change: of studies that were successful with other anti-seizure medications. And we took on the higher end of the number of patients just to be cautious.

Speaker Change: I mean, in general, the drugs that do work in primary generalized tonic-clonic seizures, when they're effective, they're pretty darn effective.

Chris Kenney: If I, you know, judging whether it's going to be as effective in focal onset seizures is anybody's guess. I would just say that when we look at the phase 2B data, and we look at the subset of patients who had focal seizures that then generalized, the data is incredibly robust. There was well over 80% reduction in those types of seizures at the high dose, and that's what gave us confidence to run the two indications, you know, in parallel. But it remains to be seen what's going to happen.

Speaker Change: Judging whether it's going to be as effective in focal onset seizures, I think, is anybody's guess.

Luke Herrmann: In terms of translatability, translatability is hard for this target because because the human nav 1.7 is different than in other animal species. We do use some genetic models and human knocking models to help us with that. But really, I think we need to run the human experiment. What we can do in animals is really understand the therapeutic index and ensure that we have, you know, we run the appropriate talk species from a regulator point of view.

Speaker Change: I would just say that when we look at the phase 2B data and we look at the subset of patients who had

Speaker Change: Folkl seizures that then generalized the data is incredibly robust, and it was well over 80% reduction in those types of seizures in the high dose.

Luke Herrmann: But we really need to run the human clinical experiment to be able to answer that question. Nice thing is you know about pain is there's an opportunity to run this earlier in human clinical development than proof of concept and some other therapeutic indications and the early studies run quite quickly as well. So I think we've made tremendous progress on this target and I don't think we're actually far away from being able to run the human experiment. Awesome. Thanks. Welcome.

Speaker Change: And that's what gave us confidence to run the two indications, you know, in parallel. But it remains to be seen what's going to happen. As far as the high dose, you know, why choose 25 milligrams? Again, that goes along with what's been learned in the field with the other drugs that first worked in focal onset seizures and then worked in...

Chris Kenney: As far as the high dose, you know, why choose 25 milligrams? Again, that goes along with what's been learned in the field with other drugs that first worked in focal onset seizures and then worked in primary generalized tonic-clonic seizures. And the path that's been laid down is that others have chosen the dose that was on the higher end of the spectrum and functional in focal onset seizures and then brought that forward. And they've been successful. And so we did the same.

Speaker Change: Primary generalized tonic-clonic seizures and the path that's been laid down is is that others have chosen the dose That was on the higher end of the spectrum and functional and focal onset seizures and then brought that forward and they've been Successful and so we did the same

Speaker Change: Thank you.

Andrew Sire: Your next question comes from the line of Andrew Sire with Jeffries. Please go ahead. Hey, good afternoon. Congrats on the execution. Thanks for the updates. I wanted to ask on PGTCS this time. Could it be possible we get data in 2025 or should we be assuming 2026 at the earliest? And I think you guys have mentioned before how the study is powered to show what other drugs show within this indication. So would it be fair to assume a 30 to 40% type placebo just a separation seizure reductions could be the bar here. Thank you. Thanks Andrew. I can maybe talk about timelines.

Speaker Change: www.globalonenessproject.org

Operator: That concludes our question and answer session, ladies and gentlemen. That concludes today's call. Thank you all for joining us. You may now disconnect.

Speaker Change: That concludes our question and answer, ladies and gentlemen. That concludes today's call. Thank you all for joining. You may now disconnect.

Speaker Change: .

Speaker Change: [inaudible]

Speaker Change: www.charlesboyk-law.com

Speaker Change: Thank you for watching.

Chris Kenney: Chris Kenny, do you want to talk about power and kind of the expectations for moving from SLS to PGTCS and some of the changes there in terms of what our expectations are. And maybe actually just the baseline seizure burden coming in as well. I think would be helpful to put that into context. But Andrew in terms of online. So we haven't guided yet on exact, which is our phase three clinical trial and primary generalized ton of chronic seizures.

Chris Kenney: I mean, if we look at the literature and the most recent studies that have been run. So now they're still running their PGTCS study, even though that drug is approved. If you look at the cost of mind where they had data very late in the commercial life of that product. You know, these are more challenging studies to run. They run much slower than the focal on set seizure studies. So although we haven't yet given guidance on it.

Chris Kenney: I just want to set expectations that these studies are slower than than what we would expect in the X total program given PGTCS is less common and the studies take longer than the focal on set seizures. And at the appropriate time, we'll be able to update in terms of guidance to top line data. But Chris, maybe you can just give because we didn't in today's prepared remarks. A little bit of background on the study design and the powering of something.

Chris Kenney: There are a few differences going from focal length seizures to primary generalized tonic colonic seizures. One is that the PGTS population in general has a lower seizure burden and it's difficult to find those patients. And so that's why you end up seeing the duration of the study take a little bit longer. And unfortunately, when the drugs work, they work really well and you need fewer patients to show efficacy. So as you look at the spectrum of what's been done in the past on the low end, you have the study that was done that's a pyramid just had about 40 patients per group.

Chris Kenney: So 40 times two. And I think the Lamotra gene had 60 patients per arm. So 60 times two for the total size. Then there are three examples of studies PGTS studies that had about 80 patients per arm. So total of about 160 patients. Two examples include perampinil and leverage arositam. And that's what we've anchored to sort of on the higher end of that spectrum of between 40 to 80 patients. I mean, the one exception that included even higher patients was was the Lakosamide study, but that was a time to event study with a different entry criteria.

Chris Kenney: So it's sort of comparing apples to oranges. But so we're on the higher end of that. And, you know, we don't, I mean, compared to folk onset seizures, we don't have preliminary data. And so our study was simply powered over, you know, compared to those three examples of previous studies that used about 80 patients per arm. Thanks.

Speaker Change: Christopher Kenney, Chad Fugere, Ian Mortimer, Chad Fugere

Unknown Attendee: Your next question comes from the line of false oil. We go on sex. Please go ahead.

Unknown Attendee: Excuse me. And this is why we cannot hear you kind of we check your line, please. Thank you.

Unknown Attendee: Operator, we can move to the next question and then we can go.

Paul Maseus: Hi. Sorry. Can you hear me? Sorry about that. I just wanted to ask a follow-up on nav 1.7 with regard to development and pain. And can you comment, you know, pending any of the animal model work, what you see as the most logical development focus for that area. What do you focus on acute development clinical strategy or a focusing perhaps on the larger chronic opportunity for us to prosecute them in parallel?

Paul Maseus: Thanks, Ian. Yeah, Pauling is really a question. I would say it's probably a bit premature for us to we haven't fully fleshed out what kind of a late stage clinical development plan would look like. Obviously we would do healthy volunteer work initially, make sure that we believe we're getting appropriate exposure where we can do some modeling and predictability that we have enough receptor occupancy from an efficacy point of view. So that would be the early work.

Paul Maseus: And then as I was mentioning earlier, the nice thing about pain is we would likely run a bunny and ectomy study, right? And those studies can be run very quickly at reasonable size in terms of powering as well. We haven't designed a study like that yet. So there's a whole bunch of questions there in terms of number of active doses and potentially active controls and other things and we'll get to all of that in advance.

Paul Maseus: But you're really asking a question more about kind of the acute and chronic longer term studies, which, you know, I think are both on the table at least based on the mechanism. There's nothing to suggest with the genetics or the mechanism that we should necessarily lean one way or another. But, but so I would say today's both both are potentially on the table. We do want to really monitor how the nav 180 program is doing and how they're doing in terms of accessing the commercial market in terms of the acute market to start.

Paul Maseus: So I think that's going to be an interesting, you know, data point for to inform us as well. So I don't have a really good, you know, definitive answer for you today because I think it's just too early and too premature, but more to come on that over the next year or two.

Unknown Attendee: Okay. Thanks Ian.

Unknown Attendee: Jordan.

Unknown Attendee: Your next question comes from the line of St. Montsack with GD Cohen. Please go ahead. Hi, guys. Thanks for taking our questions. I guess could you talk a little bit more about the design of the MEDD total program? I guess in terms of just initiating studies and enrollment and the data releases. Are you playing on staggering initiation on 1, 2, 3, or are you going to initiate them all at once? And then for the data releases, basically the same question will be released all at once, where it will be done with the study analysis complete. And then just secondly and real quickly apologies if I missed this. It's not just it'll be measured in these studies. Thanks. Thank you.

Ian Mortimer: Yeah, I'll take the first part of on the staggering and then Chris Kenney, I think it's probably helpful maybe just to go through some of the entry criteria into the study since, you know, we learned a lot from phase 2 is we're moving into the phase 3 program. I think we can kind of review some of that. We didn't have time to do that in the in the prepared remarks and then maybe you can address this as a question on on Madras.

Ian Mortimer: So we're going to we'll be staggering these studies. So just naturally, they won't start at all at the same time. So our first study we filed was that filed the protocol with FDA and that should start later this year as we've guided. And then we expect a natural stagger for the second and the third studies. And that would be our expectation on the release of data as well is that when the first study is complete and we've unblinded those data will provide those data publicly and then the second study and the third study would follow suit after that.

Ian Mortimer: So expect a stagger not not from a perspective that we're waiting for a readout on the first one before we start the second one. But so at some point they will all be running near about the same time, but we would definitely start the first one and finish that and unblind those data and provide them.

Chris Kenney: But Chris, maybe you can go through some more of the entry criteria because I think that's important for for this program and then answer the question around Madras. Sure, thanks Ian. Yeah, I would say three things about study design that should work in our favor. The first is that as we go from phase two to phase three. We'll just have one treatment group versus placebo. So that if you look at other studies that definitely helps in terms of placebo response.

Chris Kenney: The other thing is that the size of the study in the prepared remarks, we talked about a study size of 450 patients, so 225 per arm. So that's, you know, through four fold higher than than what was used in the phase two study exnova and there were some imbalances not dramatic but subtle imbalances that occurred in the exnova study. So that larger study design, you know, I think is guaranteed to iron those things out.

Chris Kenney: And then the other thing more specifically directed to the question, we're still going after moderate to severe depression. What we learned mirrors what other studies have learned, which is that if you have patients that slip in with that are slightly on the more milder end of the spectrum, even though they meet the criteria for being moderate to severe. But if they're on the milder end of the spectrum, then they can skew the data a bit.

Chris Kenney: And so we're just going to be more strict, and in terms of the cutoff that we use for the HamD, and then there are some other criteria that we're just in general going to be more strict about making sure that nobody comes in this study on the milder end of the spectrum. Those are the big changes. In terms of the modus, I mean one of the guiding principles in depression is keep it as simple as you can and that worked well with X Nova.

Chris Kenney: I mean we did actually use two scales as you know which is fortunate because it allowed us to choose the HamD to go into phase three. But we went back and forth about whether modus should be included and ultimately decided not that you know assessing depression to you know to the least amount that still led to a successful outcome was the best approach. So we're going to focus on HamD which we saw in our study had dramatically less variability and we've seen the same in other studies and that's what we're focused on. Great, thank you very much.

Dylan Ramadane: Your next question comes from the line of Laura Chico with web bush of your these please go ahead. Hi, can you hear me? Yes, we can hear you. Thank you very much for taking my question of this is Dylan on for Laura Chico. And I'm not sure if this is a question for Chris Kenney or Ian, but we noticed within the SCNA as the NAA program partner with Nercan. You're also looking at an actually candidate that's not one to have 1.6 inhibitor for focal epilepsy and we're wondering if you see positive outcomes with 352 with this also read through to the broader seizure related indications.

Ian Mortimer: Yeah, I can take that Dylan. Yeah, there's a little bit of history here, which is probably helpful in in worse work and going through so 352 is the molecule that so these are sodium channel inhibitors that came out as xenons laboratories and and were licensed as part of a transaction with Nercan and Nercan is doing the development and and paying for the development. So it's a milestone in royalty transaction for xenon so 352 is in the SCNA a day phase two clinical trials to mention right now they did run that in a in a focal onset seizure study.

Ian Mortimer: That was a small proof of concept study around 100 subjects that read out last fall and they're not moving 352 forward in in focal onset seizures. The molecule that we referred to today on the prepared remarks has a little bit of a different profile so although it's it's highly potent on nav 1.6 it's also potent on another sodium channel called nav 1.2. Whereas 352 was much more selective for 1.6 so we would consider this a dual inhibitor that has potency on both channels both channels are involved in in excitation in the brain.

Ian Mortimer: So both well validated targets this next molecule is still preclinical and as it goes into clinical development you know Nercan at that point would guide in terms of what types of studies it would go into but it would be into in to epilepsy studies as well. Is that background helpful? Yeah, thank you so much for seeing the question.

Unknown Attendee: Yep, no problem.

Marc Goodman: Your next question comes from the line of Marc Goodman with Learing Partners.

Basma Ibrahim: Please go ahead. Hi, this is Basma on for Marc. We have a question on X-Act. Could you please remind us that we should expect in terms of the efficacy of Z1111 in the primary genome eye seizures. Should we expect an efficacy in line? Is what we've seen in the focal length of seizures. We also have a question about the dose, the 25 milligram. What kind of work you've done to actually be comfortable about the use of this dose and this indication and whether you believe this dose will be efficacious or not.

Basma Ibrahim: Thank you. Great. Thanks for the question. Chris Fanny, over to you. Yeah, thanks. Thanks for the question. So as I sort of said earlier, we, I mean, one of the differences between the focal length of seizure population and the primary generalizes that we don't have preliminary data. And so we powered the exact study based upon a few different examples of studies that were successful with other anti seizure medications. And we took on a higher end of the number of patients just to be cautious.

Basma Ibrahim: I mean, in general, what the drugs that do work in primary generalized toniconic seizures when they're effective, they're pretty darn effective. If I, you know, judging whether it's going to be as effective in focal onset seizures, I think, is anybody's guess. I would just say that, you know, when we look at the phase to be data and we look at the subset of patients who had focal seizures that then generalized, the data is incredibly robust.

Basma Ibrahim: It was well over 80% reduction in those types of seizures in the high dose. And that's what gave us confidence to run the two indications, you know, in parallel. But it remains to be seen what's going to happen as far as the high dose, you know, why choose 25 milligrams. Again, that goes along with what's been learned in the field with the other drugs that first worked in focal onset seizures and then worked in primary generalized toniconic seizures.

Basma Ibrahim: And the path that's been laid down is that others have chosen the dose that was on the higher end of the spectrum and functional in focal onset seizures and then brought that forward. And they've been successful. And so we did the same.

Thank you. That concludes our question and answer.

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

You You You You You[inaudible]