X-NOVA2 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the clinical efficacy, safety, and tolerability of azetukalner as a monotherapy in adult participants diagnosed with Major Depressive Disorder (MDD)

Start Date20 Dec 2024

Sponsor / Collaborator

Xenon Pharmaceuticals, Inc.

CTIS2022-502281-25-00

/ RecruitingPhase 3

A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Focal-Onset Seizures - XPF-010-302

Start Date13 Oct 2023

Sponsor / Collaborator

Xenon Pharmaceuticals, Inc.

NCT05716100

/ RecruitingPhase 3

A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Focal-Onset Seizures

The X-TOLE3 Phase 3 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive therapy in focal-onset seizures.

Start Date09 May 2023

Sponsor / Collaborator

Xenon Pharmaceuticals, Inc.

[+1]

100 Clinical Results associated with Azetukalner

100 Translational Medicine associated with Azetukalner

100 Patents (Medical) associated with Azetukalner

Literatures (Medical) associated with Azetukalner

01 Oct 2024·EPILEPSIA

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development

Article

Author: White, H. Steve ; Johannessen, Svein I. ; Perucca, Emilio ; Tomson, Torbjörn ; Koepp, Matthias J. ; Bialer, Meir ; Perucca, Piero

Abstract:

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy‐related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3‐specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5‐HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit‐containing N‐methyl‐D‐aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain‐of‐function mutations in the GRIN1, −2A, ‐2B, or ‐2D genes; soticlestat (TAK‐935), a selective inhibitor of cholesterol 24‐hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK‐001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo‐controlled adjunctive‐therapy trial. For the other compounds, adequately powered placebo‐controlled efficacy trials have not been completed to date.

02 Jun 2024·Expert review of clinical pharmacology

A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy

Review

Author: Brigo, Francesco ; Trinka, Eugen ; Silvestrini, Mauro ; Lattanzi, Simona ; Striano, Pasquale ; Meletti, Stefano ; Matricardi, Sara

INTRODUCTION:

Epilepsies are a group of heterogeneous brain disorder, and antiseizure medications (ASMs) are the mainstay of treatment. Despite the availability of more than 30 drugs, at least one third of individuals with epilepsy are drug-resistant. This emphasizes the need for novel compounds that combine efficacy with improved tolerability.

AREAS COVERED:

A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM.

EXPERT OPINION:

Results from the phase 2b clinical trial strongly support the ongoing clinical development of azetukalner as a new ASM. Its pharmacokinetic properties support convenient once-daily dosing, eliminating the need for titration at initiation or tapering at the conclusion of treatment. CYP3A4 is the main enzyme involved in its metabolism and drug-drug interactions can affect the drug exposure. Preliminary analysis of an ongoing open-label study reveals no reported pigmentary abnormalities. The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval.

01 Nov 2023·JAMA neurology

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

Article

Importance:

Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.

Objective:

To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).

Design, Setting, and Participants:

This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.

Interventions:

Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).

Main Outcomes and Measures:

The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.

Results:

A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P &lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P &lt; .001 vs placebo; IQR, −76.7% to −14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, −61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, −37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported.

Conclusions and Relevance:

The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs.

Trial Registration:

ClinicalTrials.gov Identifier: NCT03796962

News (Medical) associated with Azetukalner

13 Jan 2025

·investor.xenon-pharma.com

Xenon Outlines Key Corporate Milestone Opportunities for 2025

– Topline data from the first Phase 3 FOS study anticipated in H2 2025 representing major milestone in support of NDA filing and potential launch of azetukalner – First of three planned Phase 3 MDD studies now initiated – Expanding ion channel portfolio includes Kv7 and Nav1.7 candidates advancing towards IND filings in 2025 VANCOUVER, British Columbia and BOSTON, Jan. 13, 2025 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq: XENE), a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics for patients in need, today outlined progress within its pipeline programs and key milestones for 2025. “Reflecting on our accomplishments in 2024, we are proud of the advancements in our late-stage clinical programs, culminating in a strong presence at AES where we presented new long-term azetukalner data from our ongoing X-TOLE open-label extension study showing sustained monthly reduction in seizure frequency and impressive seizure freedom rates in patients with epilepsy,” said Ian Mortimer, President and Chief Executive Officer of Xenon. “We also made significant progress within our early-stage portfolio, progressing multiple drug candidates targeting Kv7 and Nav1.7 into IND-enabling studies.” “Looking ahead to 2025, we anticipate a number of important milestones, particularly the first Phase 3 topline readout of azetukalner in focal onset seizures expected in the second half of 2025, representing a major inflection point for Xenon as we evolve from a clinical to commercial stage organization. Beyond epilepsy, we continue to advance azetukalner in MDD with the recent launch of our first Phase 3 study. Lastly, we expect multiple IND filings in 2025 in our early-stage programs, with the goal of initiating first-in-human trials across multiple targets,” stated Mr. Mortimer. Program Updates and Anticipated Milestones Phase 3 azetukalner clinical studies in focal onset seizures (FOS) continue to advance, with the first topline data readout anticipated in the second half of 2025. Building upon more than 600 patient-years of data to date from the ongoing X-TOLE open-label extension study, Xenon continues to generate long-term scientific evidence supporting azetukalner’s compelling efficacy and safety profile. The Phase 3 X-ACKT clinical study continues to enroll patients and is intended to support potential regulatory submissions in an additional epilepsy indication of primary generalized tonic-clonic seizures (PGTCS). The first of three planned Phase 3 clinical trials evaluating azetukalner in patients with MDD, X-NOVA2, has been initiated to support indication expansion of azetukalner in neuropsychiatry. In addition, topline results from the Mount Sinai investigator-led study of azetukalner in MDD are anticipated in the first half of 2025. Xenon continues to expand its portfolio with pre-clinical candidates targeting Kv7, Nav1.7, and Nav1.1 across various indications and anticipates filing multiple INDs, or equivalent, in 2025. Within Xenon’s partnered program, Neurocrine Biosciences is now focusing its efforts on progressing a Nav1.2/1.6 inhibitor towards human clinical trials in 2025 as a potential treatment for epilepsy. About Azetukalner Phase 3 Epilepsy Program Xenon’s Phase 3 epilepsy program includes three Phase 3 clinical trials in focal onset seizures (FOS) and primary generalized tonic-clonic seizures (PGTCS). Designed closely after the Phase 2b X-TOLE clinical trial, the Phase 3 X-TOLE clinical trials are multicenter, randomized, double-blind, placebo-controlled studies evaluating the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered orally with food as adjunctive treatment in approximately 360 patients with FOS per study. The primary efficacy endpoint is the median percent change (MPC) in monthly seizure frequency from baseline through the 12-week double-blind period (DBP) of azetukalner compared to placebo. X-ACKT is a multicenter, randomized, double-blind, placebo-controlled study evaluating the clinical efficacy, safety, and tolerability of 25 mg of azetukalner administered with food as adjunctive treatment in approximately 160 patients with PGTCS. The primary efficacy endpoint is the MPC in monthly PGTCS frequency from baseline through the 12-week DBP of azetukalner compared to placebo. Upon completion of the DBP in the Phase 3 epilepsy studies, eligible patients may enter an OLE study for up to three years. About Azetukalner Phase 3 MDD Program Xenon’s Phase 3 MDD program includes three multicenter, randomized, double-blind, placebo-controlled clinical trials to evaluate the clinical efficacy, safety, and tolerability of 20 mg of azetukalner administered orally with food over the 6-week double-blind period (DBP) as monotherapy treatment in approximately 450 patients with moderate-to-severe major depressive disorder (MDD) per study. The primary efficacy endpoint is the change from baseline in the HAM-D17 score at week 6 in patients who received azetukalner compared to placebo. Upon completion of the DBP, eligible patients may enter an OLE study for up to 12 months. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq: XENE) is a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics. We are advancing an ion channel product portfolio to address areas of high unmet medical need, including epilepsy and depression. Azetukalner, a novel, highly potent, selective Kv7 potassium channel opener, represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development for multiple indications. For more information, please visit www.xenon-pharma.com. Safe Harbor Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs, including the anticipated filing of INDs; the timing and results of our interactions with regulators; our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates; and anticipated timing of topline data readout from our clinical trials of azetukalner. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; the impact of unstable economic conditions in the general domestic and global economic markets; adverse conditions from geopolitical events; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Contacts: For Investors: Chad Fugere Vice President, Investor Relations (857) 675-7275 investors@xenon-pharma.com For Media: Colleen Alabiso Senior Vice President, Corporate Affairs (617) 671-9238 media@xenon-pharma.com Source: Xenon Pharmaceuticals Inc.

Phase 3Phase 2

06 Dec 2024

·www.globenewswire.com

Xenon Showcases New Long-Term Azetukalner Data from X-TOLE OLE Study in FOS at AES 2024

– OLE data shows sustained monthly reduction in seizure frequency, impressive seizure freedom rates, and consistent AE safety profile suggesting long-term efficacy and tolerability of azetukalner – Approximately one in three patients on drug for at least 36 months achieved seizure freedom for a period of one year or longer – Sustained monthly reductions in seizure frequency maintained at 85% at OLE study month 36 – Patient-reported survey data and literature review illustrate significant mental health and comorbidity burdens of focal onset seizures highlighting areas of unmet need for people living with epilepsy – New pre-clinical data shows Nav1.1 potentiator provides protection against spontaneous seizures and SUDEP in pre-clinical Dravet model VANCOUVER, British Columbia and BOSTON, Dec. 06, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq: XENE), a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics for patients in need, today announced new compelling long-term data from its ongoing X-TOLE open-label extension (OLE) study of azetukalner in patients with focal onset seizures (FOS) presented at the American Epilepsy Society Annual Meeting (AES 2024) taking place December 6-10, 2024 at the Los Angeles Convention Center in Los Angeles, CA. “We are excited for this opportunity to engage with the broad epilepsy community at AES 2024 and share new long-term azetukalner data from our ongoing X-TOLE open-label extension study showing compelling evidence of sustained seizure reduction and seizure freedom rates,” stated Dr. Christopher Kenney, Chief Medical Officer of Xenon. “Approximately one-third of patients who have been on azetukalner for at least 36 months achieved 100% seizure reduction, or seizure freedom, for a period of one year or longer. This is a meaningful metric for epileptologists who tell us that seizure freedom translates directly into improved quality of life for people living with epilepsy. Further, we continue to see an impressive, sustained monthly reduction in seizure frequency – approximately 85% at month 36 – while importantly maintaining a consistent safety profile that suggests azetukalner continues to be generally well-tolerated.” Dr. Kenney added, “There remains a substantial need for new, efficacious and well-tolerated epilepsy therapies, especially for those patients who continue to experience the debilitating impacts of focal seizures even while taking multiple anti-seizure medications. As we continue to build upon the foundation of strong X-TOLE results, amass a growing amount of supportive data from the ongoing open-label extension study, and drive towards Phase 3 completion, we believe that azetukalner could be paradigm-shifting in the treatment of epilepsy in the future.” Poster Presentation #2.361: Long-term Safety and Efficacy of Azetukalner, a Novel, Potent Kv7 Potassium Channel Opener in Adults With Focal Epilepsy: Update From the Ongoing 7-year Open-Label Extension of X-TOLE The results presented at AES 2024 are interim data from the X‑TOLE OLE in which participants received open‑label azetukalner at a dose of 20 mg once daily (QD) with food. Sustained reductions in seizure frequency: For ongoing OLE patients, monthly median percent change (MPC) reductions in FOS frequency ranged from 61%‑82% during month 1 to OLE study month 24 and were maintained at 85% at OLE study month 36. Patients who were receiving 1 to 2 anti-seizure medications (ASMs) at baseline experienced higher monthly MPC reductions in FOS frequency from baseline at OLE study month 36 (100% seizure reduction, n=67), compared to those receiving 3 ASMs (80.6% seizure reduction, n=80).Achieving seizure freedom: For those participants who were treated for >36 months in the OLE, 32.7% (48/147) achieved seizure freedom for a period of at least 12 months.Consistent tolerability and safety profile: Azetukalner continues to be generally well‑tolerated in the OLE, with AEs consistent with prior results in the double-blind period and other ASMs; no new safety signals were identified.Long-term retention: A total of 182 participants were treated in the OLE for ≥12 months, 165 participants were treated for ≥24 months, and 143 participants were treated for ≥36 months at the time of the analysis cutoff (October 7, 2024). Retention rates with azetukalner at 12, 24, and 36 months into the OLE study period were 66%, 60%, and 52%, respectively. “With over 600 patient-years of azetukalner exposure in people living with epilepsy – and some patients now on drug for more than 5 years – these latest long-term OLE results further validate our substantial clinical experience with azetukalner and reinforce our belief that azetukalner represents a potentially best-in-class anti-seizure medication,” stated Ian Mortimer, President and Chief Executive Officer of Xenon. “In addition to the interim long-term OLE data, we will present important results from a patient-survey and a literature review study looking at the impacts of the mental health burden and comorbidities of focal onset seizures. We will also highlight new data from our Nav1.1 potentiator program that showed protection against spontaneous seizures and SUDEP in a pre-clinical model, suggesting that targeting Nav1.1 could potentially address the underlying cause and symptoms of Dravet Syndrome,” added Mr. Mortimer. Poster Presentation #2.347: Is the Mental Health Burden of Epilepsy Under-Recognized in Patients Reporting Focal Onset Seizures? A Patient-Reported Outcomes Study Patients with epilepsy reporting FOS experience considerable mental health burden in addition to their recurring seizure burden. Most patients experienced ≥3 non-seizure symptoms despite ongoing treatment with existing anti-seizure medications, with most experiencing mood issues (e.g., depression, anxiety) that ranged from moderate to severe.The high positive screening rates for depression and anxiety, in contrast to lower self-reported physician-diagnosed depression and anxiety, suggest mental health burden may be under-recognized in patients with epilepsy reporting FOS. Poster Presentation #2.338: A Targeted Literature Review of Comorbidity Burden in Focal Onset Seizures Patients with FOS and comorbid conditions experience greater disease burden compared to those without comorbidities, highlighting an area of unmet need in this population.Enhanced understanding of the association between comorbidities, particularly mental health comorbidities like depression and the burden of FOS may enable personalized treatment and help in improving patient outcomes. Poster Presentation #3.389: Nav1.1 Potentiators Modulate Brain Rhythms Measured Through Quantitative Electrocorticography (qECoG) in a Dravet Mouse Model These data suggest Scn1a+/‑ mouse brain activity is differentiated from that in wild‑type littermates. XPC‑418, a Nav1.1 potentiator, altered brain activity in Scn1a+/‑ mice, making the phenotype more similar to that of wild‑type animals, and also changed brain activity in wild‑type mice in a dose‑ and time‑dependent manner.These pre-clinical data indicate that Nav1.1 potentiation could normalize the power spectrum phenotype of Dravet mice to the wild‑type phenotype. Poster Presentation #3.395: Selective Potentiation of Nav1.1 Channels in Dravet Mice Restores Interneuron Function and Improves Motor Function Acute dosing of XPC‑837 – an orally available, small molecule, CNS-penetrant, highly selective Nav1.1 potentiator – suppressed induced seizures in the 6Hz assay and improved motor performance in the Rotarod assay, supporting the potential for improvements in Dravet patient motor function. Chronic dosing over 14 days with XPC‑837 in chow suppressed spontaneous seizures, prevented sudden unexpected death in epilepsy (SUDEP) and increased long-term potentiation, a potential cellular correlate of learning and memory.These pre-clinical data suggest that XPC‑837 could represent a novel, mechanistically differentiated, orally available compound with the potential to provide an improved therapeutic profile for the overarching treatment of Dravet Syndrome. Scientific Exhibit Xenon is hosting a Scientific Exhibit to provide an overview of its clinical and research programs on Sunday, December 8, 2024 from 2 pm to 5 pm PT in Room 406A on level 2. In addition to the posters noted above, the exhibit will provide information related to the azetukalner Phase 3 epilepsy program, including its ongoing clinical trials in focal onset seizures and primary generalized tonic-clonic seizures. The exhibit will also feature the topline results from the Phase 2 X-NOVA clinical trial that evaluated azetukalner in major depressive disorder. Exhibit Hall In addition to Booth #1721 in the Exhibit Hall, Xenon is hosting a dedicated Mindfulness Zone (#1827) to rest, recharge, and learn more about the mental health burden associated with epilepsy. As part of Xenon’s commitment to raising awareness about mental health, visitors are invited to join the cause with donations going to the Epilepsy Foundation of America to support comprehensive mental health programming, which strives to ensure that all individuals living with epilepsy and seizure disorders have access to quality, affordable mental health care. The Exhibit Hall will open on Saturday, December 7 at 12 pm PT and close on Monday, December 9 at 2 pm PT. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq: XENE) is a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics. We are advancing an ion channel product portfolio to address areas of high unmet medical need, including epilepsy and depression. Azetukalner, a novel, highly potent, selective Kv7 potassium channel opener, represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development for multiple indications. For more information, please visit www.xenon-pharma.com. Safe Harbor Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs; and our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Contacts: For Investors:Chad FugereVice President, Investor Relations(857) 675-7275investors@xenon-pharma.com For Media:Colleen AlabisoSenior Vice President, Corporate Affairs(617) 671-9238media@xenon-pharma.com

Clinical ResultPhase 2

25 Nov 2024

·www.globenewswire.com

Xenon to Showcase New Long-Term Azetukalner Data at AES 2024

Five posters to be presented including new long-term 36-month data from the ongoing X-TOLE OLE study of azetukalner in FOS and findings around mental health and comorbidity burdens of FOSNew pre-clinical data from the Company’s Nav1.1 program VANCOUVER, British Columbia and BOSTON, Nov. 25, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq: XENE), a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics for patients in need, today announced multiple presentations at the upcoming American Epilepsy Society Annual Meeting (AES 2024), taking place December 6-10, 2024 at the Los Angeles Convention Center in Los Angeles, CA. Five posters will be presented, featuring new long-term data from the ongoing X-TOLE open-label extension study of azetukalner in patients with focal onset seizures (FOS), the mental health burden and comorbidity burdens of focal onset seizures, as well as new pre-clinical data from the Company’s early-stage Nav1.1 program. Poster Presentation #2.361: Long-term Safety and Efficacy of Azetukalner, a Novel, Potent Kv7 Potassium Channel Opener in Adults With Focal Epilepsy: Update From the Ongoing 7-year Open-Label Extension of X-TOLEJacqueline A. French, MD, New York University Grossman School of Medicine and NYU Langone HealthAuthor Session: Sunday, December 8 from 12 pm – 2 pm PT in South Hall H, Level 1 Poster Presentation #2.347: Is the Mental Health Burden of Epilepsy Under-Recognized in Patients Reporting Focal Onset Seizures? A Patient-Reported Outcomes StudyAuthor Session: Sunday, December 8 from 12 pm – 2 pm PT in South Hall H, Level 1 Poster Presentation #2.338: A Targeted Literature Review of Comorbidity Burden in Focal Onset SeizuresAuthor Session: Sunday, December 8 from 12 pm – 2 pm PT in South Hall H, Level 1 Poster Presentation #3.389: Nav1.1 Potentiators Modulate Brain Rhythms Measured Through Quantitative Electrocorticography (qECoG) in a Dravet Mouse ModelAuthor Session: Monday, December 9 from 12 pm – 2 pm PT in South Hall K, Level 1 Poster Presentation #3.395: Selective Potentiation of Nav1.1 Channels in Dravet Mice Restores Interneuron Function and Improves Motor FunctionAuthor Session: Monday, December 9 from 12 pm – 2 pm PT in South Hall K, Level 1 Scientific Exhibit Xenon is hosting a Scientific Exhibit to provide an overview of its clinical and research programs on Sunday, December 8, 2024 from 2 pm – 5 pm PT in Room 406A on level 2. Exhibit Hall Xenon is hosting booths #1721 and #1827 in the Exhibit Hall, which is scheduled to open at 12 pm PT on Saturday, December 7 and close on Monday, December 9, 2024 at 2 pm PT. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq: XENE) is a neuroscience-focused biopharmaceutical company dedicated to discovering, developing, and delivering life-changing therapeutics. We are advancing an ion channel product portfolio to address areas of high unmet medical need, including epilepsy and depression. Azetukalner, a novel, highly potent, selective Kv7 potassium channel opener, represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development for multiple indications. For more information, please visit www.xenon-pharma.com. Safe Harbor Statement This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs; and our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. Contacts: For Investors:Chad FugereVice President, Investor Relations(857) 675-7275investors@xenon-pharma.com For Media:Colleen AlabisoSenior Vice President, Corporate Affairs(617) 671-9238media@xenon-pharma.com

Clinical Study

100 Deals associated with Azetukalner

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 3	US	Xenon Pharmaceuticals, Inc.	20 Dec 2024
Epilepsy, Tonic-Clonic	Phase 3	US	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	AR	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	AU	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	AT	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	BG	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	CA	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	HR	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	CZ	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	FR	Xenon Pharmaceuticals, Inc.	14 Feb 2023

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03796962 (X-TOLE, NEWS) Manual	Not Applicable	Epilepsies, Partial	182	Azetukalner	gbotyuoajl(iuonbgqnzg) = qqpdxirqnr vsvttaodxf (vtyficqnay ) View more	Positive	06 Dec 2024
NCT03796962 (X-TOLE, CTgov)	Phase 2	Epilepsies, Partial \| Seizures	325	XEN1101 (25 mg XEN1101)	rqsfkzxeoy(doskvlasyu) = bmevsxyhoa crbnxfsrta (awqukviyot, forgxzxnqy - kwrflwuvrr) View more	-	24 Sep 2024
				XEN1101 (20 mg XEN1101)	rqsfkzxeoy(doskvlasyu) = xlfeipxdfw crbnxfsrta (awqukviyot, ffnemcumkt - vggokotnyw) View more
NCT05376150 (X-NOVA, Company_Website) Manual	Phase 2	Depressive Disorder, Major	168	Azetukalner 10mg	itblcwbpgp(jdhegyrogi) = lsbqoamkyj ypoxtkeuec (zkghcycjgh )	Positive	28 May 2024
				Azetukalner 20mg	itblcwbpgp(jdhegyrogi) = rbrjpslszp ypoxtkeuec (zkghcycjgh ) View more
NCT03796962 (X-TOLE, AAN2024)	Phase 2	Epilepsies, Partial	285	XEN1101 10mg QD	lutxgwmccy(vapoyjqjbf) = -83.4% at 18 months in the OLE vs DBP baseline hjzoffujgi (klmcmmovkw ) View more	Positive	09 Apr 2024
				XEN1101 20mg QD
AAN2024	Not Applicable	Epilepsies, Partial	-	XEN1101 25mg	xarnhivtwh(wclgxhgocx) = jzdyohacpu zsgigchrob (bseynvhxsr )	-	09 Apr 2024
				Placebo	xarnhivtwh(wclgxhgocx) = fbmjrnppod zsgigchrob (bseynvhxsr )
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	325	XEN1101	oyfdqoouzj(lfuyxioqxr) = oaqmdevdui xolhfdlftm (huirwsmyms )	Positive	03 Dec 2023
				Placebo	oyfdqoouzj(lfuyxioqxr) = sjxtnzbfix xolhfdlftm (huirwsmyms )
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	170	XEN1101 (overall)	hgrtldwqtd(xgbvniqksu) = rwhjbodsee opsurwyokr (djdqpmuwnz ) View more	Positive	03 Dec 2023
				XEN1101 (seizure-free group)	hgrtldwqtd(xgbvniqksu) = vrksppztcw opsurwyokr (djdqpmuwnz ) View more
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	275	XEN1101	gygywuijsp(dnnkurmaol) = The most common reasons for discontinuation were lack of efficacy (13.1%), adverse events (12.0%), and study withdrawal by patient (11.3%). xudztqdmsp (lahznoocqt ) View more	Positive	02 Dec 2023
NCT05376150 (X-NOVA, Corporate Publications) Manual	Phase 2	Depressive Disorder, Major	168	XEN1101 10 mg	idmqnsnpni(rujgqbbokm) = ewaviqibjz pgnniawhww (ttyanmouwx )	Positive	27 Nov 2023
				XEN1101 20 mg	idmqnsnpni(rujgqbbokm) = xfepumbebb pgnniawhww (ttyanmouwx ) View more
NCT03796962 (X-TOLE, Pubmed) Manual	Phase 2	Epilepsies, Partial	325	XEN1101 25 mg	keqiwlwowj(yraeexttdy) = vkmoolfzjo hkyafbdskr (bkwhzherkj, -80.4 to -16.9)	Positive	09 Oct 2023
				XEN1101 20 mg	keqiwlwowj(yraeexttdy) = kvfjkppqhv hkyafbdskr (bkwhzherkj, -76.7 to -14.0)

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