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XEN1101 Phase 3 epilepsy program continues to progress with X-TOLE2 and X-TOLE3 in focal onset seizures and X-ACKT in primary generalized tonic-clonic seizures; completion of patient enrollment in X-TOLE2 expected in late 2024 to early 2025 Planned “end-of-Phase 2” meeting with the FDA in April to support the initiation of XEN1101 Phase 3 program in major depressive disorder in the second half of the year Strong financial position with approximately $930 million to fully support XEN1101 Phase 3 programs in epilepsy and major depressive disorder and expected cash runway into 2027 Conference call at 4:30 pm ET today VANCOUVER, British Columbia, Feb. 29, 2024 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a neurology-focused biopharmaceutical company, today reported financial results for the fourth quarter and full year ended December 31, 2023 and provided a corporate update. Mr. Ian Mortimer, Xenon’s President and Chief Executive Officer, stated, “I am proud of the progress made across our pipeline in 2023, culminating in the release of topline data from our XEN1101 Phase 2 proof-of-concept X-NOVA clinical trial, which demonstrated clinically meaningful drug activity in depression. We are advancing XEN1101 in major depressive disorder with plans to conduct an end-of-Phase 2 meeting with the FDA in April, and we expect to initiate our Phase 3 program in the second half of this year. We also continue to evaluate other neurological indications that present a potential fit for XEN1101’s novel mechanism and product profile. Importantly, we believe the Kv7 mechanism of XEN1101 may have broad applicability, which supports our comprehensive strategy to pursue multiple streams of late-stage clinical development in epilepsy and depression.” Mr. Mortimer added, “We continue to make progress in our broad Phase 3 epilepsy programs, and we expect patient enrollment in X-TOLE2 to be completed in late 2024 to early 2025. We remain focused on executing our clinical development plans in epilepsy and are encouraged by the enthusiasm for XEN1101 from clinical investigators and the broader neurology community.” “We have also made significant advancements across our pre-clinical pipeline, leveraging our expertise in ion channel drug discovery to identify new product candidates across various targets including pain and seizure disorders. With a strong balance sheet to support our ambitious plans, we are looking forward to advancing and growing our broad pipeline, with the goal of improving outcomes for patients in areas of high unmet medical need.” Highlights and Anticipated Milestones XEN1101 XEN1101 is a novel, potent Kv7 potassium channel opener being developed for the treatment of epilepsy, major depressive disorder, or MDD, and potentially other neurological disorders. XEN1101 for Epilepsy (Focal Onset Seizures) Xenon’s XEN1101 Phase 3 epilepsy program includes two identical Phase 3 clinical trials, called 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 XEN1101 administered with food as adjunctive treatment in approximately 360 patients per study with focal onset seizures, or FOS. Xenon anticipates patient enrollment in X-TOLE2 will be completed in late 2024 to early 2025. XEN1101 for 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 XEN1101 administered with food as adjunctive treatment in approximately 160 patients with PGTCS. XEN1101 for 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 XEN1101. XEN1101 for Major Depressive Disorder 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 participating in an “end-of-Phase 2” meeting with the U.S. Food and Drug Administration in April to support the initiation of its late-stage XEN1101 clinical program in MDD, which will include three Phase 3 clinical trials, with the first Phase 3 study expected to initiate in the second half of 2024. Xenon is also evaluating other potential indications for the future development of XEN1101. 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 XEN1101 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 development candidates targeting Kv7, Nav1.1 and Nav1.7, and Xenon expects multiple candidates will enter 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. Fourth Quarter and Full Year Financial Results Cash and cash equivalents and marketable securities were $930.9 million as of December 31, 2023, compared to $720.8 million as of December 31, 2022. The increase was primarily the result of the completion of the Company’s public equity offering in December 2023. Based on current operating plans, including the completion of the XEN1101 Phase 3 epilepsy studies and fully supporting late-stage clinical development of XEN1101 in MDD, Xenon anticipates having sufficient cash to fund operations into 2027. As of December 31, 2023, there were 75,370,977 common shares and 2,173,081 pre-funded warrants outstanding. Research and development expenses were $41.1 million for the fourth quarter of 2023, and $167.5 million for the year ended 2023, compared to $34.8 million and $105.8 million for the same periods in 2022, respectively. The increase in research and development expenses for the year was primarily attributable to expenses related to Xenon's enrollment of the XEN1101 Phase 3 epilepsy clinical trials, manufacturing to support current and future clinical trials and a potential NDA submission, the completion of the X-NOVA Phase 2 MDD clinical trial, 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 $12.6 million for the fourth quarter of 2023, and $46.5 million for the year ended 2023, compared to $8.5 million and $32.8 million for the same periods in 2022, respectively. The increase in general and administrative expenses for the year was primarily attributable to personnel-related costs due to an increase in employee headcount and higher stock-based compensation expense, and an increase in professional and consulting fees. Other income was $8.7 million for the fourth quarter of 2023, and $31.4 million for the year ended 2023, compared to $7.1 million and $3.9 million for the same periods in 2022. The increase in other income for the year was primarily attributable to higher interest income and an unrealized fair value gain on trading securities recognized in 2023 compared to an unrealized fair value loss for the same period in 2022. Net loss was $44.7 million for the fourth quarter of 2023, and $182.4 million for the year ended 2023, compared to $37.4 million and $125.4 million for the same periods in 2022, respectively. The increase in net loss for the year was primarily attributable to higher research and development expenses driven by the ongoing XEN1101 Phase 3 epilepsy clinical trials, 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 fourth quarter and full year 2023 results. The audio webcast can be accessed on the Investors section of the Xenon website. Participants can access the live conference call by dialing (800) 715-9871, or (646) 307-1963 for international callers, and provide conference ID number 9376408. A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived 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 XEN1101 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 XEN1101 and our other product candidates; anticipated enrollment in our clinical trials of XEN1101 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 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. XENON PHARMACEUTICALS INC. Condensed Consolidated Balance Sheets (Expressed in thousands of U.S. dollars) December 31, December 31, 2023 2022 Assets Current assets: Cash and cash equivalents and marketable securities $638,082 $592,087 Other current assets 6,880 8,211 Marketable securities, long-term 292,792 128,682 Other long-term assets 27,044 25,166 Total assets $964,798 $754,146 Liabilities Current liabilities: Accounts payable and accrued expenses $25,974 $22,214 Other current liabilities 1,299 488 Other long-term liabilities 9,604 9,947 Total liabilities $36,877 $32,649 Shareholders’ equity $927,921 $721,497 Total liabilities and shareholders’ equity $964,798 $754,146 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 EndedDecember 31, Year EndedDecember 31, 2023 2022 2023 2022 Revenue $— $— $— $9,434 Operating expenses: Research and development 41,076 34,830 167,512 105,767 General and administrative 12,619 8,501 46,542 32,810 53,695 43,331 214,054 138,577 Loss from operations (53,695) (43,331) (214,054) (129,143)Other income 8,747 7,075 31,369 3,888 Loss before income taxes (44,948) (36,256) (182,685) (125,255)Income tax recovery (expense) 205 (1,139) 292 (118)Net loss (44,743) (37,395) (182,393) (125,373)Net loss attributable to preferred shareholders — — — (437)Net loss attributable to common shareholders $(44,743) $(37,395) $(182,393) $(124,936) Other comprehensive income (loss): Unrealized gain (loss) on available-for-sale securities $2,876 $(45) $2,923 $(2,010)Comprehensive loss $(41,867) $(37,440) $(179,470) $(127,383) Net loss per common share: Basic and diluted $(0.64) $(0.57) $(2.73) $(2.06)Weighted-average common shares outstanding: Basic and diluted 69,968,038 65,657,784 66,889,005 60,542,142 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

癫痫是神经内科重大疾病之一，发病率接近1%，中国有近1000万癫痫患者。其中，约三分之一的癫痫患者对现有药物均不敏感，被称为难治性癫痫。KCNQ钾通道包括KCNQ1 ~ KCNQ5五个亚型，其中KCNQ2是确证的癫痫治疗靶点。首个靶向KCNQ2通道的抗癫痫药物瑞替加滨（Retigabine，RTG）于2011年上市，但存在严重的剂量相关的皮肤及视网膜色素沉积等毒副作用，其原研公司葛兰素史克（GSK）基于商业原因于2017年将其主动撤市。高效但没有色素沉积等副作用是靶向KCNQ2抗癫痫药物研发的一个方向，特别随着抗抑郁等扩展适应症研究结果披露，KCNQ2近年来备受关注。派恩加滨（Pynegabine，HN37）由中国科学院上海药物研究所自主研发，已推进至临床II期研究阶段，国内权益已转让。与瑞替加滨相比，派恩加滨的化学性质、活性、药代和安全性特征均显著优化，没有色素沉积风险，在包括难治性癫痫在内的多种动物模型上显示良好抗癫痫效应（图1）。临床I期试验证明其具有良好的安全和代谢特性。派恩加滨作为新一代靶向KCNQ通道的抗癫痫药物，有望为众多难治性癫痫患者提供药物治疗新选择。上海药物所高召兵课题组围绕与神经系统重大疾病有关的离子通道为中心，致力于推进离子通道新机制、新功能研究，发现新型离子通道，研发离子通道新药。课题组在KCNQ通道相关的抗癫痫/镇痛药物发现和机制研究中与合作者共同开展了系列研究工作：建立高通量筛选体系发现一系列KCNQ小分子激动剂（Mol Pharm. 2015; Acta Pharmacol Sin. 2016; JMC. 2020）；证明激活外周KCNQ通道可有效镇痛（Pain. 2015）;揭示了KCNQ2通道小分子激动剂的亚型选择性直接受胞内信号通路调节，与细胞膜二磷酸磷脂酰肌醇（PIP2）水平直接相关（PNAS. 2013a）；结合分子模拟模拟，揭示了PIP2增强KCNQ2电压敏感性动态调节机制，发现了新的PIP2 结合位点（PNAS. 2013b）；证明一个通道结合一个小分子激动剂即可实现药理学效应（Cell Res. 2016）; 证明抗癫痫新药派恩加滨在自发性癫痫发作的点突变小鼠模型上具有较好的治疗效应，提示KCNQ2通道激动剂类药物可能对KCNQ2突变致先天性癫痫有治疗效果（Neurobiol Dis. 2022）；采用CRISPR/Cas9技术修复KCNQ2通道单点突变，率先在动物体内水平实现遗传性癫痫的基因治疗（Acta Pharmacol Sin. 2023）。派恩加滨作为新一代KCNQ2通道激动剂，理解其强效激动KCNQ2通道的分子作用机制对指导临床实验和KCNQ通道药物研发均有重要意义。为此，课题组联合浙江大学郭江涛教授开展合作研究。2023年10月19日，联合团队在Nature Communications 发表研究论文“Ligand activation mechanisms of human KCNQ2 channel”，报道了人源KCNQ2- HN37和PIP2复合物的结构，揭示了派恩加滨的分子作用机制。冷冻电镜结构显示1个KCNQ2亚基可结合2个HN37分子，表明1个KCNQ2通道最多可结合8个HN37分子；通过比较关闭态和开放态的KCNQ2的结构，并结合其它KCNQ2激动剂大麻二酚（CBD）等的结合模式，该论文对KCNQ2激动剂作用机制进行了较为全面的分析。不同于对 KCNQ2增强活性较弱的小分子激动剂RTG（KCNQ2-CaMRTG），1个KCNQ2亚基中仅结合1个RTG小分子；在KCNQ2-CaMHN37结构中，1个KCNQ2亚基结合2个HN37分子：HN37A和HN37B（图2a和b）。其中，HN37A结合于RTG结合口袋（图2c），表明它可能与RTG的激活机制相同；而HN37B结合在电压感受区（VSD）和孔道区（PD）的界面处（图2d）。结合口袋获电生理研究证实。结合更多结构和电生理研究，论文推测HN37B可能有稳定HN37A的作用，或可部分发挥PIP2的功能。派恩加滨不同于瑞替加滨的两组结合位点，以及本研究揭示的与PIP2潜在的相互作用，可能是其强效激动活性的分子基础。图1. 抗癫痫候选新药派恩加滨（Pynegabine，HN37）图2. 结合HN37的KCNQ2-CaM结构（KCNQ2-CaMHN37）浙江大学基础医学院博士生马德敏和李潇潇、上海药物所郑月明副研究员和周晓宇博士为论文的共同第一作者。浙江大学基础医学院郭江涛教授和上海药物所高召兵研究员为共同通讯作者。该工作还得到派恩加滨共同发明人上海药物所南发俊研究员, 浙江大学医学院杨巍教授、苏楠楠教授、赵国华教授、方嘉佳教授和澳门科技大学侯盼盼助理教授的大力支持；电镜数据收集工作得到浙江大学冷冻电镜中心的大力支持。本研究受国家自然科学基金、浙江省自然科学基金、国家杰出青年科学基金、国家科技创新2030重大计划和中国科学院青年创新促进会、国家重点研发计划等项目的资助。全文链接：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-42416-x本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！