Azetukalner Efficacy and Safety - Azetukalner demonstrated a 90.9% median percent change (MPC) reduction in monthly focal onset seizure (FOS) frequency after 48 months in the open-label extension (OLE) [92] - A subset of patients receiving 1-2 anti-seizure medications (ASMs) at double-blind period (DBP) baseline experienced a 100% monthly reduction in FOS frequency [92] - 38% of patients treated with azetukalner for at least 48 months achieved seizure freedom for one year or longer [92] - Azetukalner's safety and tolerability profile in the OLE remained consistent with the DBP [92, 73] - In the Phase 2b X-TOLE study, azetukalner showed statistically significant and dose-dependent seizure reduction, with up to a 52.8% median percent change from baseline [34] Commercial Opportunity and Market Insights - Xenon Pharmaceuticals has $555.3 million in cash, cash equivalents, and marketable securities as of September 30, 2025, with anticipated cash runway into 2027 [18] - An estimated 2.6 million adults in EU4 + UK, 3.0 million in Japan, and 0.8 million in the U.S have diagnosed epilepsy [95] - Focal onset seizures (FOS) represent the largest segment of the epilepsy population [95] - Up to 50% of epilepsy patients may require additional treatment options, presenting a significant commercial opportunity [102, 97] Clinical and Patient Burden - Depression is a significant burden for patients with FOS, highlighting the need for therapeutics that do not exacerbate mood disorders [92, 79] - Titration of anti-seizure medications (ASMs) poses a significant burden for both patients and healthcare professionals (HCPs), underscoring the need for simplified or no-titration ASMs [92, 87]

Core Insights - Xenon Pharmaceuticals Inc. announced new data on its commitment to epilepsy treatment, including interim 48-month data from the X-TOLE open-label extension study of azetukalner, real-world studies on depression burden, and pre-clinical data for Dravet syndrome [1][2] Group 1: Azetukalner Efficacy and Safety - The interim data from the X-TOLE study showed a monthly seizure frequency reduction of over 90% at 48 months, with a 100% reduction in patients on 1-2 anti-seizure medications (ASMs) at baseline [2][4] - Among participants treated for 48 months, 38.2% achieved at least 12 months of seizure freedom, while 10.7% maintained seizure freedom for 48 months [4] - The long-term safety profile of azetukalner was consistent with that observed during the double-blind period, indicating a favorable tolerability [5] Group 2: Real-World Studies on Depression in Epilepsy - A study found that 80.6% of patients with focal seizures reported depressed mood, highlighting the significant mental health burden among this population [7] - Newly diagnosed epilepsy patients with depression had a higher prevalence of comorbidities and an increased risk of treatment failure, emphasizing the need for tailored treatment strategies [8] - Patients with moderate to severe depression symptoms experienced a lower quality of life and higher healthcare resource utilization, reinforcing the necessity for routine depression screening in epilepsy care [9] Group 3: Pipeline and Future Directions - Xenon is preparing to share Phase 3 data from the X-TOLE2 study in early 2026, which is anticipated to be a significant milestone for the company and the epilepsy community [2] - The company is also advancing early-stage programs targeting potassium and sodium channels for potential pain treatment, indicating a broadening of its therapeutic focus [15]

Core Viewpoint - Xenon Pharmaceuticals reported a narrower loss than expected for Q3 2025, with shares increasing by approximately 9.7% since the last earnings report, outperforming the S&P 500 [1][3]. Financial Performance - The company reported a loss of $1.15 per share for Q3 2025, which was better than the Zacks Consensus Estimate of a loss of $1.16, compared to a loss of $0.81 per share in the same quarter last year [3]. - Xenon did not generate any revenues in the reported quarter, similar to the year-ago quarter, as it lacks a marketed product and only recognizes collaboration revenues from its partnership with Neurocrine Biosciences [4]. - Research and development (R&D) expenses rose by 35% year-over-year to $77.1 million, driven by costs related to late-stage studies in epilepsy and major depressive disorder (MDD), as well as increased personnel expenses [5]. - General and administrative expenses increased by 16% year-over-year to $19.3 million, primarily due to higher professional and consulting fees [6]. - As of September 30, 2025, the company had cash, cash equivalents, and marketable securities totaling $555.3 million, down from $624.8 million as of June 30, 2025, which is expected to fund operations through 2027 [7]. Market Sentiment and Estimates - Estimates for Xenon Pharmaceuticals have trended upward over the past month, indicating a positive outlook despite the current Zacks Rank of 3 (Hold) [8][10]. - The company has a poor Growth Score of F and a Momentum Score of C, with an overall VGM Score of F, placing it in the bottom 20% for value investors [9]. Industry Comparison - Xenon Pharmaceuticals is part of the Zacks Medical - Biomedical and Genetics industry, where BioMarin Pharmaceutical (BMRN) has seen a 2.6% gain over the past month, reporting revenues of $776.13 million for the last quarter, a year-over-year increase of 4.1% [11][12].

Core Insights - Xenon Pharmaceuticals Inc. is hosting an investor webinar on December 10, 2025, to present data from the American Epilepsy Society Annual Meeting, focusing on long-term data from the X-TOLE study of azetukalner and real-world data on depression in epilepsy [1][2] - Azetukalner is a novel Kv7 potassium channel opener currently in Phase 3 clinical trials for epilepsy, major depressive disorder, and bipolar depression [3] Company Overview - Xenon Pharmaceuticals is a neuroscience-focused biopharmaceutical company dedicated to drug discovery, clinical development, and commercialization of therapeutics [3] - The company is advancing a portfolio of potassium and sodium channel modulators, including Kv7 and Nav1.7 programs in Phase 1 development for pain treatment [3] Webinar Details - The webinar will take place from 10:00 to 11:00 AM Eastern Time, with a live webcast available on the company's website [2] - Participants can submit questions via chat during the webinar or in advance via email [2]

Core Insights - Xenon Pharmaceuticals Inc. is set to present multiple research findings at the American Epilepsy Society Annual Meeting (AES 2025) from December 5-9, 2025, focusing on their lead molecule azetukalner for epilepsy treatment [1][5][9] - The presentations will include long-term data from the X-TOLE open-label extension study, which supports the potential for extended seizure freedom with azetukalner [1][5][6] - Additional findings will address the impact of depression on epilepsy patients and new pre-clinical data from the NaV1.1 program targeting Dravet syndrome [1][5][9] Presentation Details - Seven posters will be presented, including: - Long-term safety and efficacy data of azetukalner in adults with focal epilepsy, with a ≥48-month interim analysis from the ongoing 7-year X-TOLE study [6] - Characterization of long-term seizure freedom in the ongoing open-label extension of X-TOLE [6] - Studies on depression symptoms among epilepsy patients and their impact on treatment outcomes [6][5] - A symposium titled "Exploring Depression and Anxiety in Epilepsy" will be held in partnership with the Epilepsy Foundation of America [5] Company Overview - Xenon Pharmaceuticals is a neuroscience-focused biopharmaceutical company dedicated to drug discovery and development of therapeutics for epilepsy and other neurological disorders [9] - The company's lead molecule, azetukalner, is a selective KV7 potassium channel opener currently in Phase 3 clinical trials for epilepsy, major depressive disorder, and bipolar depression [9] - Xenon is also advancing early-stage programs targeting potassium and sodium channels for potential pain treatment [9]

Summary of Xenon Pharmaceuticals Conference Call Company Overview - **Company**: Xenon Pharmaceuticals (NasdaqGM:XENE) - **Focus**: Neurology, specializing in drug and ion channels in the central nervous system (CNS) [4][47] Key Programs and Milestones Lead Molecule: Azetukalner - **Indications**: Epilepsy and neuropsychiatry - **Mechanism**: Potassium channel modulator - **Phase III Trials**: - XTOL II for focal onset seizures, fully enrolled with 380 subjects [11][54] - Expected data readout in early 2026 [5][12] - **Phase IIb Data**: Showed best efficacy ever seen in a clinical trial for focal onset seizures with a 35% placebo-adjusted efficacy [5][48] - **Neuropsychiatry Expansion**: - Three ongoing Phase III trials for major depressive disorder (MDD) and bipolar depression [6][49] - XNOVA II and XNOVA III for MDD, and XCEED for bipolar depression [6][49] Pain Portfolio - **New Targets**: - Nav1.7 (XEN-1701) and Kv7, both in Phase I trials [6][50] - Nav1.7 has a strong genetic basis for pain signaling [38][39] - **Future Plans**: Aim to start Phase II proof of concept studies in 2027 [42][43] Market Opportunity - **Epilepsy Market**: - 3 million Americans have epilepsy; 60% have focal onset seizures [25][69] - Approximately 1 million patients could benefit from a new treatment [25][69] - **Depression Market**: - Focus on rapid onset and impact on anhedonia, differentiating from traditional SSRIs and SNRIs [31][76] Clinical Trial Design and Expectations - **Phase III Design**: - XTOL II and XTOL III are identical studies with the same inclusion-exclusion criteria [21][64] - High power assumptions: >99% at high dose and >90% at 15 mg dose [14][57] - **Efficacy Expectations**: - Confidence in reproducibility from Phase II to Phase III based on historical data [15][58] Regulatory and Commercialization Plans - **NDA Submission**: Expected in 2026, approximately six months after XTOL II data readout [21][64] - **EMA Requirements**: Likely need both XTOL II and XTOL III for submission [21][65] - **DEA Scheduling**: All anti-seizure medications are typically scheduled; specifics will depend on final data [66][67] Additional Insights - **Adverse Event Profile**: Azetukalner is expected to have a favorable profile compared to existing treatments, with no significant weight gain or sexual dysfunction [33][77] - **Market Research**: Positive feedback from psychiatrists regarding the novel mechanism and rapidity of onset [31][75] This summary encapsulates the key points discussed during the conference call, highlighting Xenon Pharmaceuticals' strategic focus, clinical developments, market opportunities, and regulatory plans.

Xenon Pharmaceuticals Conference Call Summary Company Overview - **Company**: Xenon Pharmaceuticals (NasdaqGM:XENE) - **Focus**: Development of innovative therapies for epilepsy, psychiatry, and pain management Key Themes Discussed 1. **Lead Program - Azetukalner in Epilepsy** - Near-term phase 3 data expected in early 2026 from the fully enrolled EXTOL-two program [2][4] - Positive phase 2b data showing best efficacy in focal onset seizure studies with a severe patient population [6][7] - High confidence in phase 3 readout due to consistent inclusion-exclusion criteria and experienced clinical sites [10][11] 2. **Expansion into Psychiatry** - Ongoing phase 3 trials for major depressive disorder (MDD) and recently initiated trials for bipolar depression [2][3] - Phase 2 proof of concept study (ExNOVA) showed clear separation between active and placebo with a three-point difference on clinical scales [25][26] 3. **Emerging Early-Stage Portfolio in Pain** - Two phase 1 assets targeting NaV1.7 and Kv7, with plans to advance to phase 2 proof of concept studies in 2026 [3][50] - NaV1.7 target based on genetic studies showing patients with loss of function do not feel pain [36][37] Important Data and Insights - **Azetukalner Efficacy**: Placebo-adjusted efficacy in phase 2b ranged from teens to low 30s in monthly seizure reduction [9] - **Commercial Strategy**: Engaging with the epilepsy community and preparing for a successful launch with a Chief Commercial Officer and medical science liaisons in place [14][16] - **Market Opportunity**: Approximately 1 million patients in the U.S. with focal onset seizures are not achieving good seizure control [18] Competitive Landscape - **Market Dynamics**: Acknowledgment of multiple existing drugs in the focal onset seizure market, but belief in the unique profile of Azetukalner to differentiate from competitors [34][35] - **Regulatory Path**: Plans to file NDA next year, with Exfil and Exfil II studies included in the filing package [12][13] Pipeline Developments 1. **NaV1.7 and Kv7 Programs** - NaV1.7 in phase I study with a focus on achieving high receptor occupancy and safety [39][40] - Kv7 program showing potential analgesic effects similar to opioids [50] 2. **NaV1.1 for Dravet Syndrome** - Development of an oral small molecule to potentiate NaV1.1 channels, aiming to protect against seizures and improve survival in animal models [51][53] - Plans to initiate human clinical trials next year [54] Financial Position - **Cash Reserves**: Over $500 million in cash at the end of the last quarter, expected to sustain operations into 2027 [55]

Financial Data and Key Metrics Changes - Cash, cash equivalents, and marketable securities totaled $555.3 million as of September 30, 2025, down from $754.4 million as of December 31, 2024 [31][32] - The company anticipates having sufficient cash to fund operations into 2027 based on current operating plans [31][32] Business Line Data and Key Metrics Changes - The phase 3 XTOL-2 study of Ezetikelner for focal onset seizures has randomized 380 patients, exceeding the original goal of 360 [6][14] - The company is focused on completing the XTOL-2 study to deliver top-line data in early 2026 [14][33] Market Data and Key Metrics Changes - The company is expanding Ezetikelner's therapeutic opportunities beyond epilepsy into neuropsychiatric indications, including major depressive disorder and bipolar depression [5][20] - The XCEED trial for bipolar I and II depression is underway, with a primary efficacy endpoint based on the change from baseline in the MADRS score [21] Company Strategy and Development Direction - The company aims to file its first NDA for Ezetikelner in the U.S. following positive top-line data from the XTOL-2 study [5][33] - There is a strong focus on advancing earlier stage programs, including Nav1.7 and KV7 ion channel programs, which are now in phase 1 studies [22][24] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism for a positive outcome from the XTOL-2 study, which they believe will support the NDA submission for Ezetikelner [10][12] - The company is preparing for commercialization and anticipates a significant increase in operational expenses in 2026 as they prepare for a potential launch in 2027 [57] Other Important Information - The company has made targeted investments to prepare for commercialization and has a healthy balance sheet to support multiple registration programs [31][57] - The new Chief Financial Officer, Tucker Kelly, brings extensive experience in corporate strategy and financial planning, which will be valuable for the company's future growth [29][30] Q&A Session Summary Question: What should be expected in the top-line data release regarding efficacy and safety? - Management indicated that the top-line data will include key efficacy endpoints and overall comments on safety and tolerability, similar to previous releases [36][37] Question: What was the screen failure rate for XTOL-2? - Management stated that the screen failure rate trended as expected, with reasons for dropouts being consistent with prior experiences [38][39] Question: How does the efficacy of Ezetikelner compare to other therapies? - Management emphasized that while efficacy is important, the overall profile, including tolerability and ease of use, will drive prescribing decisions [42][43] Question: What is the rationale for using MADRS in the XCEED trial? - The decision to use MADRS was based on precedents in bipolar studies, as it has been commonly used for assessing depressive symptoms in this population [47][48] Question: What are the expectations for the early-stage pipeline? - Management expects to provide updates on the phase 1 studies for XEN1701 and XEN1120 in early 2026, with a focus on safety and tolerability [52][53]

Financial Performance - For the nine months ended September 30, 2025, the company recognized revenue of $7.5 million, compared to nil for the same period in 2024[57]. - The company incurred a net loss of $240.6 million for the nine months ended September 30, 2025, compared to a net loss of $168.6 million for the same period in 2024[58]. - As of September 30, 2025, the company had an accumulated deficit of $1,140.1 million[58]. - Collaboration revenue for the nine months ended September 30, 2025, was $7.5 million, a significant increase from $0 in the same period in 2024[77]. - Net cash used in operating activities was $197.6 million for the nine months ended September 30, 2025, compared to $127.0 million for the same period in 2024, reflecting increased expenses[88]. - For the nine months ended September 30, 2025, net cash provided by financing activities was $3.6 million, compared to nil for the same period in 2024[91]. Research and Development - The Phase 3 X-TOLE2 study of azetukalner in focal onset seizures has completed patient enrollment with 380 patients randomized, with topline data anticipated in early 2026[56]. - The company is advancing azetukalner for multiple indications, including major depressive disorder and bipolar depression, with ongoing Phase 3 studies[56]. - A Phase 1 study for NBI-921355, a selective inhibitor of voltage-gated sodium channels, is underway as part of a collaboration with Neurocrine Biosciences[57]. - The company expects research and development expenses to increase substantially as it continues to invest in product candidates and clinical studies[66]. - Direct external costs related to azetukalner increased by $13.1 million (44.3%) for the three months and $41.5 million (54.5%) for the nine months ended September 30, 2025, compared to the same periods in 2024[78]. - The company expects to incur significant expenses and increasing operating losses for the foreseeable future as it prepares for the potential commercial launch of azetukalner[84]. Expenses - Research and development expenses increased by $20.1 million (35.2%) for the three months and $62.3 million (41.3%) for the nine months ended September 30, 2025, compared to the same periods in 2024[78]. - General and administrative expenses rose by $2.6 million (15.4%) for the three months and $6.7 million (13.1%) for the nine months ended September 30, 2025, compared to the same periods in 2024[79]. - The company anticipates an increase in general and administrative expenses as it expands its operating activities and prepares for commercialization[69]. Cash and Securities - As of September 30, 2025, the company had cash and cash equivalents and marketable securities of $555.3 million[81]. - As of September 30, 2025, the company had U.S. dollar denominated cash and cash equivalents and marketable securities of $497.3 million and Canadian dollar denominated cash and cash equivalents and marketable securities of CAD$79.6 million[95]. - A 100 basis point increase in interest rates would have resulted in approximately a $2.7 million decrease in the fair value of the company's marketable securities as of September 30, 2025[98]. Foreign Currency Risk - The company is exposed to foreign currency exchange rate risk, particularly with transactions denominated in Canadian dollars[96]. - The company does not currently hedge its exposure to foreign currency exchange rates, assuming the risk of future gains or losses[97]. Strategic Focus - The company is focused on maintaining existing collaborations and establishing new ones, which may generate milestone payments and royalties[90]. - The company is expanding its research and development and initiating pre-commercial and commercial activities, which will impact headcount growth and associated costs[90]. - The company plans to prepare for the potential commercial launch of azetukalner and invest significantly in its development[63]. Other Information - There have been no material changes in the company's significant contractual obligations as of September 30, 2025, compared to those disclosed in the Annual Report on Form 10-K[92]. - As of October 30, 2025, the company had 77,275,005 common shares issued and outstanding, along with various outstanding warrants and stock options[93].

Financial Performance - Cash, cash equivalents, and marketable securities were $555.3 million as of September 30, 2025, down from $754.4 million as of December 31, 2024[13] - Net loss for Q3 2025 was $90.9 million, compared to a net loss of $62.8 million for the same period in 2024[18] - Revenue for the nine months ended September 30, 2025, was $7,500,000, compared to $0 for the same period in 2024[24] - Net loss for the nine months ended September 30, 2025, was $240,649,000, compared to a net loss of $168,645,000 in 2024, indicating a 42.7% increase in losses[24] - Basic and diluted net loss per common share for the nine months ended September 30, 2025, was $(3.05), compared to $(2.17) for the same period in 2024[24] - Comprehensive loss for the nine months ended September 30, 2025, was $238,560,000, compared to $167,232,000 in 2024, representing a 42.6% increase[24] Expenses - Research and development expenses for Q3 2025 were $77.1 million, an increase of $20.1 million compared to $57.0 million in Q3 2024[13] - General and administrative expenses for Q3 2025 were $19.3 million, up from $16.7 million in Q3 2024, reflecting an increase of $2.6 million[18] - Research and development expenses increased to $213,239,000 for the nine months ended September 30, 2025, up from $150,922,000 in 2024, representing a 41.4% increase[24] - General and administrative expenses rose to $57,564,000 for the nine months ended September 30, 2025, compared to $50,899,000 in 2024, a 13.1% increase[24] - Total operating expenses for the nine months ended September 30, 2025, were $270,803,000, up from $201,821,000 in 2024, reflecting a 34.2% increase[24] Clinical Development - The Phase 3 X-TOLE2 study of azetukalner in focal onset seizures has completed patient enrollment with 380 patients randomized, with topline data expected in early 2026[7] - The company is conducting three Phase 3 clinical studies evaluating azetukalner for major depressive disorder, with approximately 450 patients per study[12] - The Phase 1 studies for Nav1.7 and Kv7 pain programs are currently underway, focusing on developing non-opioid treatments for pain[12] Cash Flow and Financial Strategy - Xenon anticipates having sufficient cash to fund operations into 2027 based on current operating plans[13] - Other income for Q3 2025 was $6.1 million, down from $10.6 million in Q3 2024, primarily due to lower interest income[18] - Other income for the nine months ended September 30, 2025, was $23,132,000, down from $32,935,000 in 2024, a decrease of 29.6%[24] - Other comprehensive income included an unrealized gain on available-for-sale securities of $2,089,000 for the nine months ended September 30, 2025, compared to $1,413,000 in 2024[24] Leadership Changes - The company appointed Tucker Kelly as Chief Financial Officer to lead finance strategy ahead of the anticipated commercialization of azetukalner[10]