XEN-901

点击上方蓝字关注我们 引言 电压门控钠通道（Naᵥ）作为可兴奋细胞（神经元、心肌细胞、骨骼肌细胞）产生动作电位的核心分子，其功能异常与癫痫、疼痛、心律失常、肌肉疾病等多种疾病密切相关。哺乳动物中已鉴定出 9 种 Naᵥ亚型（Naᵥ1.1-Naᵥ1.9），具有组织特异性表达特征与独特生物物理特性，为亚型选择性药物开发提供了基础。本文基于《Nature Reviews Drug Discovery》2024 年综述，系统梳理 Naᵥ通道的结构功能、致病机制、亚型特异性治疗策略及药物研发进展，为生信技术辅助的精准靶向治疗提供参考。 关注[Nicole生信]，解锁更多生信研究经典案例、核心分析流程和技术干货，助力生信研究与临床转化。 文献解读 英文标题：Voltage-gated sodium channels in excitable cells as drug targets 中文标题：作为药物靶点的可兴奋细胞中的电压门控钠通道 发表期刊：Nature Reviews Drug Discovery 发表时间：2025.05.01 影响因子：101.8/中科院一区 研究背景 Naᵥ通道功能异常源于基因突变（功能获得性 GOF / 功能缺失性 LOF）或表达调控紊乱，长期以来非选择性 Naᵥ抑制剂（如卡马西平、苯妥英）虽广泛用于癫痫等疾病治疗，但因缺乏亚型特异性，易引发心血管、中枢神经系统等不良反应。随着分子生物学与结构生物学的发展，Naᵥ亚型的组织分布与功能特异性逐渐明确，亚型选择性抑制剂、反义寡核苷酸（ASO）、基因治疗等精准策略应运而生，为克服传统药物局限、提升治疗安全性提供了新方向。 研究路线和方法 01 整体研究路线 Naᵥ通道结构与亚型特征解析→ 疾病关联机制（基因突变 / 表达异常）挖掘→ 亚型特异性治疗策略设计（小分子抑制剂、ASO、基因治疗）→ 体外（细胞系 / 原代细胞）与体内（动物模型）疗效验证→ 临床转化与安全性评估→ 生信技术辅助靶点优化与药物开发。 02 核心研究方法 结构与功能研究：冷冻电镜解析 Naᵥ通道三维结构，膜片钳技术检测通道电流（瞬时电流 Iₙₐₜ、持续电流 Iₙₐₚ、复发性电流 Iₙₐᵣ），分子对接预测药物结合模式；疾病模型构建：CRISPR-Cas9 构建基因敲除 / 敲入小鼠模型（如 Dravet 综合征 Scn1a⁺/⁻小鼠）、患者来源诱导多能干细胞（iPSC）分化可兴奋细胞模型；药物筛选与优化：高通量电生理筛选平台鉴定亚型选择性化合物，结构修饰优化药物亲和力与特异性，表面等离子体共振（SPR）验证靶点结合能力；多组学与生信分析：整合 TCGA、GEO 等数据库的疾病多组学数据，筛选 Naᵥ通道相关差异表达基因，GO/KEGG 通路富集分析，构建药物疗效预测模型；临床研究：多中心随机对照试验评估药物疗效与安全性，心血管结局试验（CVOT）验证长期获益。 01 Naᵥ通道的结构特征与亚型分布 Naᵥ通道由 pore-forming α 亚基与辅助 β 亚基组成，α 亚基含四个同源结构域（DI-DIV），每个结构域包含 6 个跨膜螺旋（S1-S6），其中 S1-S4 构成电压传感模块（VSM），S5-S6 及胞外连接区形成孔道模块（PM）。9 种 Naᵥ亚型具有严格的组织特异性分布： 中枢神经系统（CNS）：Naᵥ1.1、Naᵥ1.2、Naᵥ1.6（维持兴奋性 - 抑制性平衡）； 周围神经系统（PNS）：Naᵥ1.6、Naᵥ1.7、Naᵥ1.8、Naᵥ1.9（参与疼痛信号传导）； 骨骼肌：Naᵥ1.4（调控肌肉收缩）； 心肌：Naᵥ1.5（维持心脏动作电位）。 图 1：Naᵥ通道的保守结构域 02 亚型特异性致病机制与疾病关联 不同 Naᵥ亚型的功能异常与特定疾病直接相关，核心关联如下： Naᵥ1.1（SCN1A）：LOF 突变导致 Dravet 综合征、热性惊厥等癫痫脑病，GOF 突变引发部分癫痫亚型； Naᵥ1.2（SCN2A）：GOF 突变与早发性癫痫脑病相关，LOF 突变关联孤独症谱系障碍（ASD）； Naᵥ1.4（SCN4A）：GOF 突变导致先天性肌强直、高钾型周期性麻痹，LOF 突变引发低钾型周期性麻痹； Naᵥ1.5（SCN5A）：LOF 突变导致布鲁加达综合征，GOF 突变引发长 QT 综合征 3 型（LQT3）； Naᵥ1.6（SCN8A）：GOF 突变导致癫痫脑病，LOF 突变与失神癫痫相关； Naᵥ1.7（SCN9A）：GOF 突变引发遗传性红斑肢痛症、阵发性剧痛症，LOF 突变导致先天性无痛症； Naᵥ1.8（SCN10A）：GOF 突变关联小纤维神经病变，参与慢性疼痛维持； Naᵥ1.9（SCN11A）：GOF 突变与小纤维神经病变相关，调控神经元静息膜电位。 图 2：Naᵥ通道亚型的主要表达部位 03 癫痫与神经系统疾病的 Naᵥ靶向治疗 （1）Naᵥ1.1 相关癫痫 ASO 疗法：STK-001（zorevunersen）通过靶向 SCN1A 基因的非 productive 剪接体，提升功能性 Naᵥ1.1 蛋白表达，在 Dravet 综合征小鼠模型中减少癫痫发作并延长生存期，临床 I/IIa 期显示癫痫频率显著降低； 基因治疗：ETX101 通过 AAV 载体递送工程转录因子，特异性上调 GABA 能神经元中 SCN1A 表达，小鼠模型中改善癫痫表型，目前进入 I/II 期临床； venom-derived 肽：Hm1b 通过延迟 Naᵥ1.1 失活增强通道功能，在 Dravet 综合征啮齿动物模型中减少癫痫负荷。 （2）Naᵥ1.6 相关癫痫 小分子抑制剂：NBI-921352（CNS 穿透性芳基磺酰胺类）对 Naᵥ1.6 具有高选择性，动物模型中展现抗癫痫活性，进入 II 期临床； 持续电流抑制剂：Prax562 靶向 Naᵥ1.6 的 Iₙₐₚ与 Iₙₐᵣ电流，减少神经元异常放电，在 SCN8A 相关癫痫模型中抑制癫痫发作，处于 II 期临床。 图3：Naᵥ通道靶向治疗策略 04 疼痛的 Naᵥ亚型特异性干预 （1）Naᵥ1.7 抑制剂 芳基 / 酰基磺酰胺类：PF-05089771 对 Naᵥ1.7 选择性超 1000 倍，术后疼痛 II 期试验显示有效；GEN-3565 为外周限制性抑制剂，动物模型中展现强效镇痛作用； 毒素衍生物：STX（石房蛤毒素）衍生物 ST-2262 对人 Naᵥ1.7 具有纳摩尔级亲和力，非人灵长类动物中缓解热痛；ST-2427 进入 I 期临床，耐受性良好。（2）Naᵥ1.8 抑制剂 小分子药物：VX-548（suzetrigine）获 FDA 批准用于中重度急性疼痛，III 期试验显示疗效优于安慰剂，与氢可酮 / 对乙酰氨基酚相当；LTGO-33 等新型抑制剂通过稳定通道失活状态减少神经元放电，进入 I 期临床； 机制特点：Naᵥ1.7 与 Naᵥ1.8 协同调控伤害性神经元动作电位，Naᵥ1.7 介导阈下去极化，Naᵥ1.8 主导动作电位上升相，联合抑制可能增强镇痛效果。 图 4：Naᵥ1.7 与 Naᵥ1.8 在伤害性神经元中的协同作用 05 心血管与肌肉疾病的治疗进展 （1）心律失常 长 QT 综合征 3 型：美西律、氟卡尼等钠通道阻滞剂通过抑制 Naᵥ1.5 的持续电流，缩短 QT 间期；雷诺嗪对心肌组织具有选择性，减少心律失常风险； 布鲁加达综合征：奎尼丁可改善心电图异常，但疗效个体差异大；基因治疗通过上调 Naᵥ1.5 分子伴侣 MOG1 表达，增加细胞膜通道密度，小鼠模型中逆转疾病表型。（2）肌肉疾病 先天性肌强直：美西律为一线治疗，通过抑制 Naᵥ1.4 的异常持续电流缓解肌肉僵硬；拉莫三嗪、雷诺嗪等可作为替代方案； 周期性麻痹：碳酸酐酶抑制剂（如二氯苯磺胺）减少麻痹发作频率；蜘蛛毒素可阻断 Naᵥ1.4 的 ω 电流，为低钾型周期性麻痹提供新型治疗思路。 06 药物开发挑战与未来方向 核心挑战：亚型选择性不足导致的脱靶毒性（如 Naᵥ1.5 抑制引发心律失常）、神经元代偿性兴奋性上调、部分亚型（如 Naᵥ1.9）异源表达困难； 技术突破：冷冻电镜解析 Naᵥ通道与药物结合的原子结构，指导精准药物设计；机器学习辅助预测化合物亚型选择性； 新型策略：ASO 靶向调控通道表达、基因编辑修复突变、肽毒素改造提升特异性、通道 trafficking 抑制剂（如调控 CRMP2 SUMO 化）。 新手复刻 01 样本准备 收集疾病相关 Naᵥ通道亚型的多组学数据（基因组、转录组、蛋白质组），包括患者样本与公共数据库（TCGA、GEO、gnomAD）数据；获取药物处理后的细胞系表达谱与电生理数据；整理 Naᵥ通道亚型的序列与结构数据（PDB 数据库）。 02 生信分析基础 掌握 R 语言基础与 limma、DESeq2 包进行差异表达基因筛选；利用 Clustal Omega 进行 Naᵥ亚型序列比对，分析保守结合位点；通过 CADD 工具预测突变有害性；使用 ggplot2 绘制突变分布热图、药物 - 靶点结合模式图。 03 进阶生信分析 利用 Cytoscape 构建 Naᵥ通道相关蛋白互作网络；结合 STRING 数据库挖掘下游信号通路；通过机器学习算法（随机森林、LASSO 回归）整合多组学数据，构建药物疗效预测模型；利用 GROMACS 进行分子动力学模拟，验证药物 - 靶点结合稳定性；通过 GO/KEGG 通路富集分析，挖掘突变相关功能通路。 04 实验验证 通过 Sanger 测序验证 Naᵥ通道突变；膜片钳技术检测通道电流变化；Western blot 验证蛋白表达与磷酸化水平；在 iPSC 分化的可兴奋细胞模型中验证药物疗效；动物模型中评估化合物的体内活性与安全性。 小结 本研究系统解析了 Naᵥ通道的亚型特异性功能、致病机制及治疗应用，明确了小分子抑制剂、ASO、基因治疗等策略的临床价值，为可兴奋细胞相关疾病的精准治疗提供了全面依据。生信技术在靶点优化、药物设计与疗效预测中发挥关键作用，助力克服亚型选择性不足等核心挑战。你在 Naᵥ通道相关疾病研究中是否关注过特定亚型（如 Naᵥ1.7、Naᵥ1.8）的功能？对肽毒素改造或 ASO 疗法的临床转化前景有何见解？欢迎交流！ 关注[Nicole生信]，解锁更多生信研究经典案例、核心分析流程和技术干货，助力生信研究与临床转化。 END 往  期  回  顾  Cell 重磅发布💪：血管类器官发育全景图谱 IF 50.0 《Nature Medicine》神作！浙大一院牵头，单细胞测序法助力 CD19+BCMA CAR-T 攻克难治性 SLE ！IF 50.0《Nature Medicine》顶刊速递！宾夕法尼亚大学团队用 “单细胞测序”，解锁 CD4+ T 细胞与 CAR-T 免疫关联！ 点个在看你最好看

– Phase 3 epilepsy program advancing with X-TOLE2 topline FOS data anticipated in H2 2025 – Long-term azetukalner results from X-TOLE open-label extension study in FOS to be presented at AES – Phase 3 MDD program on track with X-NOVA2 study expected to initiate by year-end – Expanding ion channel portfolio includes multiple candidates advancing towards IND filings in 2025 – Recent appointment of Matt Ronsheim, experienced pharmaceutical executive joining Xenon’s senior executive team as Chief Operating Officer – Conference call at 4:30 pm ET today VANCOUVER, British Columbia and BOSTON, Nov. 12, 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 provided a business update and reported financial results for the third quarter ended September 30, 2024. “Xenon’s leadership in the Kv7 landscape is unmatched as our lead molecule, azetukalner, represents the only highly potent, selective Kv7 potassium channel opener in development for multiple indications that is backed by long-term efficacy and safety data with over 600-patient years of exposure in patients living with epilepsy. Importantly, we generated highly compelling double-blind efficacy data that we believe demonstrates the best placebo-adjusted results in focal onset seizure patients, and excitement around azetukalner is building as we continue to progress toward the X-TOLE2 topline data readout expected in the second half of 2025,” stated Ian Mortimer, President and Chief Executive Officer of Xenon. “Within the X-TOLE open-label extension study, we are seeing patients – some who have been on azetukalner for more than 5 years – experience the long-term benefits of seizure freedom and improved quality of life, as well as a favorable tolerability profile and we are excited to present new 36-month data at the American Epilepsy Society annual meeting next month.” “Beyond epilepsy, we have a high degree of confidence in the broader applicability of azetukalner with our first Phase 3 trial in MDD expected to initiate by year-end, while continuing to increase the breadth of our pipeline as we progress our early-stage programs with the advancement of multiple candidates towards IND filings in 2025,” added Mr. Mortimer. Quarterly Business Highlights and Anticipated Milestones Azetukalner Clinical Development 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. Xenon is currently developing azetukalner for the treatment of epilepsy, including focal onset seizures (FOS) and primary generalized tonic-clonic seizures (PGTCS), as well as major depressive disorder (MDD), while exploring applicability in other neuropsychiatric disorders. Epilepsy Programs Phase 3 FOS studies continue to advance, with the first topline data readout from X-TOLE2 anticipated in the second half of 2025. The Phase 3 FOS clinical trials are multicenter, randomized, double-blind, placebo-controlled studies evaluating the clinical efficacy, safety, and tolerability of azetukalner in patients with FOS.Phase 3 X-ACKT clinical study is currently enrolling patients and is intended to support potential regulatory submissions in an additional epilepsy indication of PGTCS. This multicenter, randomized, double-blind, placebo-controlled trial is evaluating the clinical efficacy, safety and tolerability of azetukalner in patients with PGTCS.Building upon the 600 patient-years of drug exposure to date, Xenon continues to generate long-term scientific evidence demonstrating azetukalner’s compelling efficacy and safety profile in the ongoing X-TOLE open-label extension (OLE) study.The Company continues to present azetukalner data at leading medical conferences and congresses, including the recent 15th European Epilepsy Congress (EEC), Epilepsy Foundation Pipeline Conference, and AMCP Nexus 2024.Five abstracts were accepted for presentation at the upcoming American Epilepsy Society (AES 2024) annual meeting in Los Angeles, CA from December 6-10. The Company plans to showcase new data from the ongoing azetukalner OLE in FOS and anticipates presenting updated pre-clinical data from its Nav1.1 program. MDD Program X-NOVA2, the first of three Phase 3 clinical trials evaluating azetukalner in patients with MDD, is expected to initiate before the end of the year.Xenon presented Phase 2 X-NOVA data at the Psych Congress, which took place from October 29- November 2.The Company continues to support the investigator-sponsored Phase 2 proof-of-concept study of azetukalner in MDD led by Icahn School of Medicine at Mount Sinai. Patient enrollment for this study is now complete and results are anticipated in the first half of 2025. Early-Stage Pipeline: Next Generation Ion Channel Modulators As leaders in the small molecule ion channel space, Xenon continues to expand its portfolio by leveraging its extensive expertise to discover and develop potassium and sodium channel therapeutics, including candidates targeting Kv7, Nav1.7, and Nav1.1 across various indications with the goal of filing multiple INDs, or equivalent, in 2025. IND-enabling work is underway with multiple Kv7 development candidates. Kv7 may have utility in a broad range of therapeutic indications including seizures, pain, and neuropsychiatric disorders, such as MDD.IND-enabling work is underway with a lead Nav1.7 development candidate. Nav1.7 is an important pain-related target, based on strong human genetic validation, that may represent a new class of medicines without the limitations of opioids.The Company expects to nominate a lead candidate within its Nav1.1 program in 2025. Pre-clinical data suggests that targeting Nav1.1 could potentially address the underlying cause and symptoms of Dravet Syndrome. Corporate Xenon continues to attract top talent with extensive biopharmaceutical experience, including the recent addition of Matthew D. Ronsheim, Ph.D. as Chief Operating Officer and a member of the Xenon senior executive team. Partnered Program As part of Xenon’s ongoing collaboration with Neurocrine Biosciences to develop treatments for epilepsy, a Phase 2 clinical trial is evaluating NBI-921352 (formerly XEN901) in an orphan pediatric epilepsy (SCN8A-DEE), and the next lead candidate, a Nav1.2/1.6 inhibitor, is in IND-enabling studies with the intent to progress into human clinical trials in 2025 as a potential treatment for FOS. Third Quarter Financial Results Cash and cash equivalents and marketable securities were $803.3 million as of September 30, 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 September 30, 2024, there were 75,794,409 common shares and 2,173,081 pre-funded warrants outstanding.Research and development expenses for the quarter ended September 30, 2024 were $57.0 million, compared to $42.9 million for the same period in 2023. The increase of $14.1 million was primarily attributable to increased expenses related to the azetukalner Phase 3 epilepsy clinical trials and manufacturing activities, pre-clinical and discovery programs to advance multiple potential drug candidates targeting Kv7, Nav1.7, and Nav1.1, and increased personnel-related costs due to an increase in employee headcount and higher stock-based compensation expense.General and administrative expenses for the quarter ended September 30, 2024 were $16.7 million, compared to $12.8 million for the same period in 2023. The increase of $3.9 million was primarily attributable to personnel-related costs due to an increase in employee headcount and higher stock-based compensation expense.Other income for the quarter ended September 30, 2024 was $10.6 million, compared to $7.1 million for the same period in 2023. The increase of $3.5 million was primarily attributable to higher interest income.Net loss for the quarter ended September 30, 2024 was $62.8 million, compared to $48.5 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 and pre-clinical and discovery programs, as well as 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 third quarter results. A listen-only webcast can be accessed on the Investors section of the Xenon website, with a replay available following the event. Participants can access the conference call by dialing (800) 715-9871 or (646) 307-1963 for international callers and referencing conference ID 7128308. About the Azetukalner Phase 3 Epilepsy Program Xenon’s Phase 3 epilepsy program includes three ongoing 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 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 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 DBP of azetukalner compared to placebo. Upon completion of the double-blind period in the Phase 3 epilepsy studies, eligible patients may enter an OLE study for up to three years. 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 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 XENON PHARMACEUTICALS INC. Condensed Consolidated Balance Sheets (Expressed in thousands of U.S. dollars) September 30, December 31, 2024 2023Assets Current assets: Cash and cash equivalents and marketable securities$654,015 $638,082 Other current assets 5,624 6,880 Marketable securities, long-term 149,317 292,792 Other long-term assets 26,945 27,044 Total assets$835,901 $964,798 Liabilities Current liabilities: Accounts payable and accrued expenses$28,308 $25,974 Other current liabilities 1,387 1,299 Other long-term liabilities 8,399 9,604 Total liabilities$38,094 $36,877 Shareholders’ equity$797,807 $927,921 Total liabilities and shareholders’ equity$835,901 $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 September 30, Nine Months Ended September 30, 2024 2023 2024 2023Operating expenses: Research and development$56,970 $42,880 $150,922 $126,436 General and administrative 16,706 12,804 50,899 33,923 73,676 55,684 201,821 160,359 Loss from operations (73,676) (55,684) (201,821) (160,359)Other income 10,566 7,065 32,935 22,622 Loss before income taxes (63,110) (48,619) (168,886) (137,737)Income tax recovery 320 157 241 87 Net loss (62,790) (48,462) $(168,645) $(137,650) Other comprehensive income (loss): Unrealized gain on available-for-sale securities$3,548 $346 $1,413 $47 Comprehensive loss$(59,242) $(48,116) $(167,232) $(137,603) Net loss per common share: Basic and diluted$(0.81) $(0.73) $(2.17) $(2.09)Weighted-average common shares outstanding: Basic and diluted 77,926,205 66,002,163 77,730,644 65,862,661