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]

NCT05718817 / Enrolling by invitationPhase 3

A Multicenter, Open-label, Long-term, Safety, Tolerability, and Efficacy Study of XEN1101 in Subjects Diagnosed With Epilepsy

This study will evaluate the long term safety, tolerability, PK, and efficacy of XEN1101 25 mg QD taken orally in subjects with Focal Onset Seizures (FOS) or Primary Generalized Tonic-Clonic Seizures (PGTCS) for the treatment of seizures for up to 3 years.

Start Date25 Apr 2023

Sponsor / Collaborator

Xenon Pharmaceuticals, Inc.

[+1]

NCT05667142 / 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 Primary Generalized Tonic-Clonic Seizures

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in primary generalized tonic-clonic seizures (PGTCS).

Start Date14 Feb 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 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

01 Aug 2023·Acta pharmacologica Sinica

Functional characterization and in vitro pharmacological rescue of KCNQ2 pore mutations associated with epileptic encephalopathy.

Article

Author: Tian, Fu-Yun ; Li, Ping ; Yang, Chuan-Yan ; Shen, Yan-Wen ; Yang, Gui-Mei ; Gao, Zhao-Bing ; Yuan, Hui

Mutations in the KCNQ2 gene encoding K_V7.2 subunit that mediates neuronal M-current cause a severe form of developmental and epileptic encephalopathy (DEE). Electrophysiological evaluation of KCNQ2 mutations has been proved clinically useful in improving outcome prediction and choosing rational anti-seizure medications (ASMs). In this study we described the clinical characteristics, electrophysiological phenotypes and the in vitro response to KCNQ openers of five KCNQ2 pore mutations (V250A, N258Y, H260P, A265T and G290S) from seven patients diagnosed with KCNQ2-DEE. The KCNQ2 variants were transfected into Chinese hamster ovary (CHO) cells alone, in combination with KCNQ3 (1:1) or with wild-type KCNQ2 (KCNQ2-WT) and KCNQ3 in a ratio of 1:1:2, respectively. Their expression and electrophysiological function were assessed. When transfected alone or in combination with KCNQ3, none of these mutations affected the membrane expression of KCNQ2, but most failed to induce a potassium current except A265T, in which trace currents were observed when co-transfected with KCNQ3. When co-expressed with KCNQ2-WT and KCNQ3 (1:1:2), the currents at 0 mV of these mutations were decreased by 30%-70% compared to the KCNQ2/3 channel, which could be significantly rescued by applying KCNQ openers including the approved antiepileptic drug retigabine (RTG, 10 μM), as well as two candidates subjected to clinical trials, pynegabine (HN37, 1 μM) and XEN1101 (1 μM). These newly identified pathologic variants enrich the KCNQ2-DEE mutation hotspots in the pore-forming domain. This electrophysiological study provides a rational basis for personalized therapy with KCNQ openers in DEE patients carrying loss-of-function (LOF) mutations in KCNQ2.

12 Dec 2022·Expert opinion on pharmacotherapy

Current and future pharmacotherapy options for drug-resistant epilepsy

Review

Author: Mula, Marco ; Elkommos, Samia

INTRODUCTION:

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.

AREAS COVERED:

The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.

EXPERT OPINION:

Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

News (Medical) associated with Azetukalner

28 May 2024

·www.biospace.com

Xenon Pharmaceuticals Presents Data from Phase 2 X-NOVA Clinical Trial of Azetukalner in Major Depressive Disorder at the American Society of Clinical Psychopharmacology 2024 Annual Meeting

VANCOUVER, British Columbia, May 28, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neuroscience-focused biopharmaceutical company, announced data presentations highlighting azetukalner (XEN1101) clinical data in major depressive disorder (MDD) at the American Society of Clinical Psychopharmacology (ASCP) 2024 Annual Meeting in Miami, FL. Mr. Ian Mortimer, Xenon’s President and Chief Executive Officer, stated, “We are pleased to present these data from our Phase 2 proof-of-concept X-NOVA study of azetukalner in MDD at the ASCP meeting. The X-NOVA results demonstrated a clinically meaningful reduction in depression, in addition to an early onset of action, a significant reduction in anhedonia, and a potentially differentiated safety pro azetukalner as compared to other antidepressants. These compelling data, along with azetukalner’s novel mechanism of action, support the potential of azetukalner to have a differentiated pro the treatment of depression.” Mr. Mortimer continued, “We are looking forward to connecting with ASCP attendees and continuing to raise awareness of azetukalner’s potentially unique attributes and highlight our late-stage clinical work in MDD, starting with the initiation of our Phase 3 MDD program in the second half of this year.” Xenon’s Presentations at ASCP: Oral Presentation: “Efficacy and Safety of Azetukalner (XEN1101), a Novel, Kv7 Potassium Channel Opener in Adults With Moderate to Severe Major Depressive Disorder: Results From the Phase 2 Proof-of-Concept X-NOVA Study” Presenter: Dr. Joe McIntosh, Senior Vice President, Clinical Development, Xenon Pharmaceuticals May 28, 2024 at 2 pm ET in Salon 3 Poster: “Efficacy and Safety of Azetukalner (XEN1101), a Novel, Kv7 Potassium Channel Opener in Adults With Moderate to Severe Major Depressive Disorder: Results From the Phase 2, Proof-of-Concept X-NOVA Study” May 29, 2024 at 11:15 am to 1 pm ET in Salon 4 The Company’s presentations summarize clinical data from its topline results from the Phase 2 proof-of-concept X-NOVA clinical trial, which evaluated the clinical efficacy, safety, and tolerability of 10 mg and 20 mg of azetukalner in 168 patients with moderate to severe MDD. Summary of Efficacy Data: The primary endpoint of the study was a change in the Montgomery-Åsberg Depression Rating Scale, or MADRS, at week 6. The mean reduction was 13.90 in the placebo group, 15.61 in the 10 mg group and 16.94 in the 20 mg group. A clear dose response and a clinically meaningful, but not statistically significant, 3.04 difference between placebo and the azetukalner 20 mg groups (P=0.135) was observed. At week 1, the mean reduction in MADRS score from baseline (exploratory endpoint) was significantly different between placebo and azetukalner 20 mg groups (4.88 vs 7.54; P=0.047), demonstrating early onset of efficacy. The mean reduction in the Hamilton Depression Rating Scale, or HAM-D17, score from baseline to week 6 (pre-specified exploratory endpoint) was significantly different between placebo and azetukalner 20 mg groups (10.2 vs 13.3; difference –3.1, P=0.042). The mean reduction in the Snaith-Hamilton Pleasure Scale, or SHAPS, score from baseline to week 6 (secondary endpoint) was significantly different between placebo and azetukalner 20 mg groups (5.30 vs 7.77; difference –2.46, P=0.046). There were no statistically significant differences in change from baseline BAI total scores to week 6 between placebo and azetukalner groups. At baseline, the X-NOVA population, on average, demonstrated minimal to mild symptoms of anxiety (baseline mean BAI total score ≤15). In a post hoc analysis, amongst those participants with moderate to severe BAI scores (≥16) at baseline, numerical improvements were noted in the change from baseline BAI total scores to week 6 in the 20 mg azetukalner group compared to the placebo group (15.38 vs. 9.36; difference –6.02). Statistical significance was achieved in reporting of at least minimally improved symptoms of depression as assessed by physicians using the Clinical Global Impression of Improvement (CGI-I) (P=0.004) in the azetukalner 20 mg group compared to placebo. Summary of Safety and Tolerability Data: Azetukalner was well tolerated with a low incidence of treatment-emergent adverse events (TEAEs), and no serious TEAEs were reported in either dose group. The most commonly reported TEAEs in the azetukalner 20 mg group included dizziness (17.9%), somnolence (10.7%), headache (8.9%), and disturbance in attention (8.9%), compared to the placebo group which reported dizziness (7.3%), somnolence (1.8%), headache (12.7%), and disturbance in attention (0%). Rates of discontinuation were similar across all treatment arms and rates of discontinuation owing to TEAEs were low with three patients in the azetukalner 20 mg group (5.4%) compared to two patients in the placebo group (3.6%). Azetukalner was not associated with notable weight gain or sexual dysfunction. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq:XENE) is a neuroscience-focused biopharmaceutical company committed to discovering, developing, and commercializing innovative therapeutics to improve the lives of people living with neurological and psychiatric disorders. We are advancing a novel product pipeline to address areas of high unmet medical need, including epilepsy and depression. For more information, please visit . 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 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; 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 enrollment in our clinical trials of azetukalner and the timing thereof. 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 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 pandemics, epidemics and other public health crises on our research and clinical development plans and timelines and results of operations, including impact on our clinical trial sites, collaborators, regulatory agencies and related review times, and contractors who act for or on our behalf; 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: Jodi Regts Xenon Corporate Affairs (604) 484-3353 media@xenon-pharma.com

Clinical ResultPhase 2ASCO

09 May 2024

·www.globenewswire.com

Xenon Pharmaceuticals Reports First Quarter 2024 Financial Results and Provides Corporate Update

Phase 3 epilepsy program continues to progress with anticipated completion of patient enrollment in X-TOLE2 in late 2024 to early 2025 Successful “end-of-Phase 2” interactions with FDA in MDD; Phase 3 program on track to initiate in the second half of the year Azetukalner now the international nonproprietary name (INN) and United States adopted name (USAN) for XEN1101 Conference call at 4:30 pm ET today VANCOUVER, British Columbia, May 09, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neuroscience-focused biopharmaceutical company, today reported financial results for the first quarter ended March 31, 2024 and provided a corporate update. Mr. Ian Mortimer, Xenon’s President and Chief Executive Officer, stated, “I am excited to announce that we have received approval for the use of ‘azetukalner’ as the nonproprietary, or generic, name for XEN1101, recognizing its novel Kv7 mechanism of action. This is an important milestone for Xenon, representing another step forward as we advance azetukalner towards commercialization.” Mr. Mortimer continued, “We have made significant advancements in our azetukalner MDD program over this past quarter, including reaching alignment with the FDA on key features of our Phase 3 program. Supported by the data generated from our Phase 2 proof-of-concept X-NOVA clinical trial demonstrating clinically meaningful drug activity in depression, we believe azetukalner has the potential to offer a differentiated and competitive profile in MDD based on its unique mechanism of action and a potential benefit on anhedonia, a key co-morbidity of depression. We look forward to initiating our Phase 3 program in the second half of this year, with the goal of potentially providing a new therapeutic option to address the unmet medical need that remains in major depressive disorder.” Mr. Mortimer added, “We recently hosted two oral presentations at the American Academy of Neurology annual meeting where we were met with neurologists and epileptologists who continue to express significant excitement about the unique mechanism of azetukalner and the compelling clinical data we have generated to date in both epilepsy and MDD. We look forward to continuing to showcase azetukalner at medical conferences throughout the remainder of this year.” Highlights and Anticipated Milestones Azetukalner (XEN1101) Clinical Development Programs Xenon announced that the United States Adopted Names (USAN) Council and the World Health Organization (WHO) International Nonproprietary Names (INN) expert committee have approved “azetukalner” as the nonproprietary, or generic, name for XEN1101. Azetukalner is a novel, potent Kv7 potassium channel opener being developed for the treatment of epilepsy, major depressive disorder, and potentially other neurological disorders. Epilepsy (Focal Onset Seizures) Xenon’s Phase 3 epilepsy program in focal onset seizures, or FOS, includes two identical Phase 3 clinical trials, X-TOLE2 and X-TOLE3, that are designed closely after the Phase 2b X-TOLE clinical trial. These multicenter, randomized, double-blind, placebo-controlled trials are evaluating the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered with food as adjunctive treatment in approximately 360 patients per study with FOS. Xenon anticipates patient enrollment in X-TOLE2 will be completed in late 2024 to early 2025. Epilepsy (Primary Generalized Tonic-Clonic Seizures) Xenon’s Phase 3 X-ACKT clinical trial is intended to support potential regulatory submissions in an additional epilepsy indication of primary generalized tonic-clonic seizures, or PGTCS. This multicenter, randomized, double-blind, placebo-controlled trial is evaluating the clinical efficacy, safety, and tolerability of 25 mg of azetukalner administered with food as adjunctive treatment in approximately 160 patients with PGTCS. Epilepsy (Open-Label Extension) Upon completion of the double-blind period in X-TOLE2, X-TOLE3, or X-ACKT, eligible patients may enter an open-label extension, or OLE, study for up to three years. In addition, the ongoing X-TOLE Phase 2b OLE has been extended from five to seven years and continues to generate important long-term data for azetukalner. Major Depressive Disorder, or MDD In November 2023, Xenon reported topline results from the Phase 2 proof-of-concept X-NOVA clinical trial, which evaluated the clinical efficacy, safety, and tolerability of 10 mg and 20 mg of XEN1101 in 168 patients with moderate to severe MDD. Xenon anticipates presenting the X-NOVA topline data at the annual meeting of the American Society of Clinical Psychopharmacology (ASCP) taking place May 28-31, 2024 in Miami, FL. Based on “end-of-Phase 2” interactions with the U.S. Food and Drug Administration, Xenon continues to anticipate that the first of three Phase 3 clinical trials will be initiated in the second half of 2024. In addition, Xenon is collaborating with the Icahn School of Medicine at Mount Sinai to support an ongoing investigator-sponsored Phase 2 proof-of-concept, randomized, parallel-arm, placebo-controlled multi-site study of azetukalner for the treatment of MDD in approximately 60 subjects. Other Pipeline Opportunities Xenon continues to leverage its extensive ion channel expertise and drug discovery capabilities to identify validated drug targets and develop new product candidates. The near-term focus is on developing Kv7 channel openers, Nav1.7 inhibitors and Nav1.1 openers, with the goal of advancing multiple candidates into IND-enabling studies in 2024 and 2025. Partnered Program: NBI-921352 Xenon has an ongoing collaboration with Neurocrine Biosciences to develop treatments for epilepsy. Neurocrine Biosciences has an exclusive license to XEN901, now known as NBI-921352, a selective Nav1.6 sodium channel inhibitor. A Phase 2 clinical trial is ongoing evaluating NBI-921352 in patients aged between 2 and 21 years with SCN8A developmental and epileptic encephalopathy. First Quarter Financial Results Cash and cash equivalents and marketable securities were $885.4 million as of March 31, 2024, compared to $930.9 million as of December 31, 2023. Based on current operating plans, including the completion of the azetukalner Phase 3 epilepsy studies and fully supporting late-stage clinical development of azetukalner in MDD, Xenon anticipates having sufficient cash to fund operations into 2027. As of March 31, 2024, there were 75,459,681 common shares and 2,173,081 pre-funded warrants outstanding. Research and development expenses were $44.3 million for the first quarter of 2024, compared to $39.5 million for the same period in 2023. The increase in research and development expenses was primarily attributable to manufacturing activities for the azetukalner program to support current and future clinical trials and a potential NDA submission, increased personnel-related costs due to an increase in employee headcount, and higher stock-based compensation expense. These increases were partially offset by a decrease in expenses for the XEN496 program as a result of Xenon's decision in early 2023 to no longer pursue the clinical development of XEN496. General and administrative expenses were $14.8 million for the first quarter of 2024, compared to $9.5 million for the same period in 2023. The increase in general and administrative expenses was primarily attributable to personnel-related costs due to an increase in employee headcount and higher stock-based compensation expense, an increase in professional and consulting fees, and information technology costs related to ongoing business activities. Other income was $11.5 million for the first quarter of 2024, compared to $7.6 million for the same period in 2023. The increase in other income was primarily attributable to higher interest income, partially offset by a decrease in the unrealized fair value gain on trading securities. Net loss was $47.9 million for the first quarter of 2024, compared to $41.7 million for the same period in 2023. The increase in net loss was primarily attributable to higher research and development expenses driven by the azetukalner program, and increased personnel-related costs and stock-based compensation expense across the organization, partially offset by an increase in interest income. Conference Call Information Xenon will host a conference call and webcast today at 4:30 pm Eastern Time (1:30 pm Pacific Time) to discuss its first quarter results. The audio webcast can be accessed on the Investors section of the Xenon website. Participants are encouraged to pre-register for the conference call in order to obtain a conference passcode and unique PIN. Participants may pre-register at any time, including up to and after the call start time. Those without internet access, or unable to pre-register, may dial in toll-free to 1 (888) 500-3691, or 1 (646) 307-1951 for international callers. A replay of the webcast will be posted on the Xenon website approximately one hour after the conclusion of the event and will remain available for approximately one month. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq:XENE) is a neuroscience-focused biopharmaceutical company committed to discovering, developing, and commercializing innovative therapeutics to improve the lives of people living with neurological and psychiatric disorders. We are advancing a novel product pipeline to address areas of high unmet medical need, including epilepsy and depression. 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; 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; anticipated enrollment in our clinical trials of azetukalner and the timing thereof; and our expectation that we will have sufficient cash to fund operations into 2027. 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 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 pandemics, epidemics and other public health crises on our research and clinical development plans and timelines and results of operations, including impact on our clinical trial sites, collaborators, regulatory agencies and related review times, and contractors who act for or on our behalf; 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. XENON PHARMACEUTICALS INC. Condensed Consolidated Balance Sheets (Expressed in thousands of U.S. dollars) March 31, December 31, 2024 2023Assets Current assets: Cash and cash equivalents and marketable securities$699,602 $638,082 Other current assets 7,602 6,880 Marketable securities, long-term 185,836 292,792 Other long-term assets 25,983 27,044 Total assets$919,023 $964,798 Liabilities Current liabilities: Accounts payable and accrued expenses$20,900 $25,974 Other current liabilities 1,323 1,299 Other long-term liabilities 9,102 9,604 Total liabilities$31,325 $36,877 Shareholders’ equity$887,698 $927,921 Total liabilities and shareholders’ equity$919,023 $964,798 XENON PHARMACEUTICALS INC. Condensed Consolidated Statements of Operations and Comprehensive Loss (Expressed in thousands of U.S. dollars except share and per share amounts) Three Months Ended March 31, 2024 2023Operating expenses: Research and development$44,250 $39,516 General and administrative 14,791 9,535 59,041 49,051 Loss from operations (59,041) (49,051)Other income 11,522 7,614 Loss before income taxes (47,519) (41,437)Income tax expense (412) (290)Net loss$(47,931) $(41,727) Other comprehensive income (loss): Unrealized gain (loss) on available-for-sale securities$(1,692) $1,180 Comprehensive loss$(49,623) $(40,547) Net loss per common share: Basic and diluted$(0.62) $(0.63)Weighted-average common shares outstanding: Basic and diluted 77,594,599 65,724,681 Contacts: For Investors: Chad Fugere Vice President, Investor Relations (857) 675-7275 investors@xenon-pharma.com For Media: Jodi Regts Xenon Corporate Affairs (604) 484-3353 media@xenon-pharma.com

Phase 2Phase 3Financial Statement

16 Apr 2024

·www.biospace.com

Xenon Pharmaceuticals Showcases XEN1101 at the American Academy of Neurology 2024 Annual Meeting

VANCOUVER, British Columbia, April 16, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neuroscience-focused biopharmaceutical company, announced two oral presentations highlighting XEN1101 clinical data at the American Academy of Neurology (AAN) 2024 Annual Meeting in Denver, CO. Mr. Ian Mortimer, Xenon’s President and Chief Executive Officer, stated, “We are excited that our abstracts focused on XEN1101, including interim data from the ongoing X-TOLE open-label extension study and an overview of the impact of disease severity on responder rates in the X-TOLE Phase 2b study, were selected as oral presentations at this year’s annual meeting of the American Academy of Neurology. We are grateful to our epilepsy key opinion leaders Dr. Jacqueline French and Dr. Roger Porter for presenting the XEN1101 data. This is an important opportunity for us to connect with leading neurologists to highlight our late-stage clinical work in both epilepsy and major depressive disorder.” Xenon’s Oral Presentations at AAN Oral Presentation #005 (French et al.) “Interim, Long-term, Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update from an Ongoing Open-label Extension of a Phase 2b Study (X-TOLE) in Adults with Focal Epilepsy.” Session 19: Epilepsy Clinical Trials and Long-term Studies Oral Presentation #004 (Porter et al.) “The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults With Focal Epilepsy (X-TOLE).” Session 19: Epilepsy Clinical Trials and Long-term Studies Xenon is also hosting Booth #1797 in the AAN Exhibit Hall, which runs until Wednesday, April 17, 2024 at 4:00 pm MT. About Xenon Pharmaceuticals Inc. Xenon Pharmaceuticals (Nasdaq:XENE) is a neuroscience-focused biopharmaceutical company committed to discovering, developing, and commercializing innovative therapeutics to improve the lives of people living with neurological and psychiatric disorders. We are advancing a novel product pipeline to address areas of high unmet medical need, including epilepsy and depression. For more information, please visit . 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 product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our XEN1101; the timing and results of our interactions with regulators; our ability to successfully develop and obtain regulatory approval of XEN1101; anticipated enrollment in our clinical trials of XEN1101 and the timing thereof. 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 XEN1101, 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 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 pandemics, epidemics and other public health crises on our research and clinical development plans and timelines and results of operations, including impact on our clinical trial sites, collaborators, regulatory agencies and related review times, and contractors who act for or on our behalf; 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 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: Jodi Regts Xenon Corporate Affairs (604) 484-3353 media@xenon-pharma.com

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100 Deals associated with Azetukalner

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy, Tonic-Clonic	Phase 3	US	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	AU	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	IT	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	PL	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	PT	Xenon Pharmaceuticals, Inc.	14 Feb 2023
Epilepsy, Tonic-Clonic	Phase 3	ES	Xenon Pharmaceuticals, Inc.	14 Feb 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05376150 (X-NOVA, Company_Website) Manual	Phase 2	Depressive Disorder, Major	168	Azetukalner 10mg	arldthqlia(wwdjuwtbnt) = wdrwonvdwh rhcsorgiai (nubcbvqavo )	Positive	28 May 2024
				Azetukalner 20mg	arldthqlia(wwdjuwtbnt) = gglujjfbur rhcsorgiai (nubcbvqavo ) View more
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	325	XEN1101	ejtarhgcep(teixdoxmbk) = zrsrhhmbtx ektdgvbjln (lwgxgvrzam )	Positive	03 Dec 2023
				Placebo	ejtarhgcep(teixdoxmbk) = cmgjktcaar ektdgvbjln (lwgxgvrzam )
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	170	XEN1101 (overall)	gjpremrfvd(ouvzmmkoga) = jhlnlhesyv czdpqmtwqi (qqrtgjecbx ) View more	Positive	03 Dec 2023
				XEN1101 (seizure-free group)	gjpremrfvd(ouvzmmkoga) = ghqwlqzrdz czdpqmtwqi (qqrtgjecbx ) View more
NCT03796962 (X-TOLE, AES2023) Manual	Phase 2	Epilepsies, Partial	275	XEN1101	bpqpnetzti(ontcxsuxsg) = The most common reasons for discontinuation were lack of efficacy (13.1%), adverse events (12.0%), and study withdrawal by patient (11.3%). isqljspkwg (afbrdunnbd ) View more	Positive	02 Dec 2023
NCT05376150 (X-NOVA, Corporate Publications) Manual	Phase 2	Depressive Disorder, Major	168	XEN1101 10 mg	yfcrerjvsj(glqyhzhsjs) = jwffudqvws ctbczownir (cwdotftpjc )	Positive	27 Nov 2023
				XEN1101 20 mg	yfcrerjvsj(glqyhzhsjs) = aqtrrvvfgt ctbczownir (cwdotftpjc ) View more
NCT03796962 (X-TOLE, Pubmed) Manual	Phase 2	Epilepsies, Partial	325	XEN1101 25 mg	izuaeivoqr(dwrushwsuu) = jqgpatarxi jovyhfieho (ikdjaarysd, -80.4 to -16.9)	-	09 Oct 2023
				XEN1101 20 mg	izuaeivoqr(dwrushwsuu) = yyfvjonqrx jovyhfieho (ikdjaarysd, -76.7 to -14.0)
X-TOLE (AAN2023)	Phase 2	Epilepsies, Partial	285	XEN1101 20 mg	biknchnftj(cywhrnylip) = The most common TEAEs were dizziness, headache, somnolence, weight increased, fall, gait disturbance, fatigue, confusional state, aphasia, and memory impairment. No TEAEs of pigmentary abnormalities were reported. Two patients experienced TEAEs of urinary retention (1 mild, 1 moderate, possibly drug related, but both patients continued the medication) jquilkldbu (gqfgibiczd ) View more	-	25 Apr 2023
X-TOLE (AAN2022)	Phase 2	Epilepsies, Partial	325	XEN1101 10mg	tianamyvrv(ncrpijlble) = ohzzdefkff htomfcarwc (jktihqqslw ) View more	Positive	03 May 2022
				XEN1101 20mg	xseedgphdd(enuzjkurtq) = grfkcqgyoz cnvicoxvpt (qgemiurzgi )

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