Tetrodotoxin

【原创文章】 hERG绿灯≠心脏安全绿灯：多通道评价与CIPA模型如何重构IND申报策略 长期以来，hERG IC50几乎成了药物心脏安全性评价的“代名词”。然而，越来越多的证据表明，仅凭hERG判断心脏致心律失常风险，准确率可能不足七成。据HESI Pro-Arrhythmia Working Group在2021年发表的多中心研究，仅以hERG IC50为标准区分TdP阳性与阴性药物的准确率约为68%，而引入多通道（Nav1.5、Cav1.2）及动作电位模拟后，准确率跃升至92%以上。（Source: HESI Pro-Arrhythmia Working Group, Clinical Pharmacology & Therapeutics, 2021） 这意味着，超过三成的化合物可能在hERG的“绿灯”下潜伏着致命的心电危机。 前几篇文章中，我们借自动膜片钳的高通量战役、清醒犬遥测的代谢陷阱，层层剥开了心脏安全评价的复杂性。今天，我们把逻辑推向更为宏大的框架——多通道选择性评价与CIPA综合致心律失常预测模型。本文将用一场“hERG完美但心脏风险崩塌”的典型战役，向你展示北京向新立如何在这个新范式下，为IND申报构建铜墙铁壁。 心脏电生理的“四重奏”：不只hERG一个主角 心肌动作电位是由钠、钙、钾等离子流精细编织的交响乐。传统上只把注意力放在I_Kr（hERG）上，是因为它确实是最易受药物抑制、后果最严重的电流之一。但心脏安全的“乐谱”上，还有至少三个同等重要的声部： I_Na（Nav1.5）：峰钠电流主导动作电位0期除极，晚钠电流则参与2期平台期的维持。抑制峰钠会使除极减缓、传导阻滞；而增强或延缓晚钠电流的灭活会延长动作电位时程，并与hERG抑制协同制造复极离散。 I_CaL（Cav1.2）：L型钙电流是平台期的主要内向离子流，也是兴奋-收缩耦联的关键。药物若同时抑制hERG和Cav1.2，可能呈现代偿性QTc缩短或“假安全”信号，但心肌细胞内钙稳态早已被打破，收缩功能障碍和触发活动暗流涌动。 I_Ks（Kv7.1）：慢激活延迟整流钾电流是复极储备的重要组成。单独抑制I_Ks往往影响有限，但当I_Kr已被抑制时，I_Ks的额外阻断会暴发严重复极延长——这正是许多药物在特定心率或电解质紊乱下风险陡增的根源。 现实中的小分子药物很少只“眷顾”一个通道。即使hERG IC50高达30 µM，若同时对Nav1.5或Cav1.2有显著作用，动作电位的净时程变化可能是非线性的、剂量依赖性的、使用频率依赖性的，远非单一数值可以概括。 从ICH S7B到CIPA倡议：监管科学的“换装” 2005年ICH S7B/E14的颁布，把hERG体外实验和临床TQT研究写进了全球药品研发的DNA。但这套框架的运行代价巨大：TQT研究成本高企，且临床中观测到QTc延长却未必等于有TdP风险。 2013年，由FDA、EMA、PMDA、学术界及工业界联合发起的CIPA（Comprehensive In Vitro Proarrhythmia Assay）倡议，提出了全新的评估范式：不再以“QTc延长”为直接终点，而是以“致心律失常风险”为核心，通过三个阶段数据整合—— 多通道离子流抑制数据（hERG、Nav1.5、Cav1.2等）； 基于人心室肌细胞模型的硅基动作电位模拟（如O’Hara-Rudy模型），预测净效应； 人诱导多能干细胞来源心肌细胞的场电位记录（MEA或阻抗），作为确证。 最终生成综合致心律失常风险评分。 2020年ICH E14/S7B问答正式纳入CIPA的思路，允许在特定条件下用非临床综合数据替代TQT研究或免除TQT。这意味着深度多通道电生理评价不再是可选项，而是加速IND、节省数千万临床投入的战略级武器。 【案例独立模块】一场“完美hERG”项目的滑铁卢 以下案例源于北京向新立生物医药真实经历，已对客户信息做脱敏处理。 # 项目开局 一家初创Biotech开发一款共价Kras G12D抑制剂，靶向胰腺癌。项目在早期即引入我们进行心脏安全评估。体外数据堪称“梦幻”： hERG IC50 > 30 µM（手动膜片钳，HEK293-hERG）； 预测治疗游离浓度Cmax,free约0.05 µM，安全窗口 >600倍； 按照传统标准，心脏安全性毫无顾虑。 团队已经准备以此数据直接递交Pre-IND会议资料。 # 向新立科学顾问的建议 我们的科学顾问提出：“G12D的共价弹头在结构上含有一个α,β-不饱和酰胺，极有可能与钠通道的半胱氨酸残基发生非选择性共价结合。强烈建议在进入毒理批之前，补充Nav1.5峰钠与晚钠电流的自动膜片钳多浓度测试，并在兔浦肯野纤维上进行动作电位记录。” # 出乎意料的发现 多通道筛选结果令人震惊： 该化合物对Nav1.5峰钠电流的IC50高达25 µM，影响甚微； 但它显著增强晚钠电流（I_NaL），在5 µM浓度下I_NaL幅度增大超过300%； 同时，该分子对Cav1.2表现出中等抑制，IC50约4.5 µM。 这意味着一场“离子流混战”：晚钠电流增加使动作电位时程倾向于延长，而L型钙电流抑制则使复极有缩短和平台期塌陷的趋势。两者的角力在不同心率下呈现截然不同的结果。 在兔浦肯野纤维的记录中： 1 Hz刺激频率下，动作电位时程APD90轻微缩短（-7%），看似安全； 但当刺激频率降至0.5 Hz（模拟心动过缓），APD90反而显著延长22%，并出现早期后除极（EAD）样电位波动——这正是TdP的前驱电生理事件； 进一步将0.5 Hz的数据输入O’Hara-Rudy心室细胞模型进行硅基模拟，系统输出高致心律失常风险评分。 # 故事的结局 客户拿着这些数据重新审视先导化合物，决定在一个非关键的苯环位点引入极性基团，削弱Nav1.5晚钠增强效应，同时保留G12D活性。三代优化后，重复动作电位及硅基模拟，EAD信号消失，综合风险评分降至“低”。该项目最终成功提名PCC，并向FDA提交了包含完整多通道与动作电位数据的Pre-IND资料，获得监管方对心脏安全性策略的高度认可。 向新立统计：2024-2025年，我们为19个项目执行了“hERG + 多通道 + 浦肯野纤维 + In Silico模拟”的综合评估包，其中4个项目的hERG IC50本已“安全”，却在多通道整合评估中被发现隐藏风险，早期干预避免了临床阶段的灾难性后果。（来源：北京向新立生物医药《2025心脏安全整合评价白皮书》） 向新立多通道与CIPA整合平台：为决策注入算法级洞察 北京向新立生物医药搭建的平台，并非仅做实验，而是将电生理数据转化为可预测、可比对的风险量化结论。 # 1. 全离子通道筛选矩阵 我们在手动和自动膜片钳平台上并行提供hERG、Nav1.5（峰/晚）、Cav1.2、Kv7.1（I_Ks）、Kv4.3（I_to）、Kir2.1（I_K1）等标准通道的浓度-效应曲线，并可应客户需求扩展至HCN（I_f）、TRPM4等特殊靶点。每次实验均附带严格的溶媒对照及阳性药（如E-4031、维拉帕米、TTX等）数据。 # 2. 离体动作电位记录与复极异质性评估 采用兔浦肯野纤维和豚鼠心室肌两种模型，在微电极或光学标测下捕获动作电位形态、复极离散度和传导速度。特别适用于探测多通道混合效应带来的非线性变化。 # 3. 人源iPSC心肌细胞（hiPSC-CM）验证 与CIPA框架对应，我们配备MEA系统，记录hiPSC-CM的场电位时程（FPD）作为QTc的体外替代终点。既可独立评估，也可作为多通道筛选与硅基模拟的“生物验证层”。 # 4. 硅基模拟与报告生成 内部开发并验证了基于O’Hara-Rudy动态心室细胞模型的模拟平台，输入多通道IC50值后，自动生成动作电位波形、APD90变化、跨壁复极离散度及EAD概率。所有模拟参数均有严格边界条件，输出报告可直接用于监管沟通文档。 据Frost & Sullivan《2025年全球离子通道药物安全性评价市场展望》，能够提供从多通道筛选到硅基模拟的整合服务商仅占市场的不到8%，而北京向新立已为国内多家头部Biotech输出此类高级分析，成为行业差异化的关键优势。 心脏安全评价的终极逻辑：不要被“hERG幻觉”绑架 hERG太容易被窄化为一个数值，但心脏不是一个简单的电阻器。当你推进一个“hERG clean”的分子进入临床，却意外遭遇QTc信号或心律失常时，回过头看，往往是多通道的复杂交互、代谢产物的脱靶效应、或者复极储备的耗尽给了你沉重一击。 北京向新立生物医药的支柱页《药物心脏安全性评价全景指南》，正是要从分子到动物、从实验到算法，为你描绘出心脏安全的完整地图。无论你的项目处于苗头化合物阶段，还是即将IND，我们都能用数据和模型，帮助你做出最高质量的科学决策。 向新立：拒绝单点评价，构建你的心脏安全“数字孪生” 联系科学顾问，获取《多通道与综合致心律失常风险评估白皮书》以及CIPA适用性分析模板，为你的分子生成专属风险画像。一次全面的多通道评价，或许就是你管线中最具性价比的一笔投资。 立即访问[药物心脏安全性评价支柱页],免费下载行业白皮书，或预约免费项目咨询。 作者简介 赵长胜 北京向新立生物医药有限责任公司首席科学撰稿人、市场策略顾问，宁夏大学生命科学学院硕士导师。 在全球知名公司北京向新立生物CRO心脏安全药理部门工作逾10年，直接领导超过50个新药的心脏电生理及综合风险评估项目，深度参与CIPA倡议的数据对标和验证工作。他在多通道选择性分析、浦肯野纤维动作电位记录及In Silico心脏模型应用领域拥有丰富的实操与监管沟通经验，现任向新立内容与学术策略负责人，致力于将复杂的心脏安全科学转化为可落地、可获批的研发决策。 向新立心脏安全专题持续更新中： 支柱页：《药物心脏安全性评价全景指南：从hERG机制到IND申报》 已发布集群：《一次hERG“脱靶”，让年销数十亿的明星药消失》《高通量不会说谎：一次自动膜片钳筛掉2000个“定时炸弹”的实录》《当体外安全是假象——清醒犬遥测如何纠正认知偏差》《hERG绿灯≠心脏安全绿灯：多通道评价与CIPA模型重构IND申报策略》 后续深度文章将聚焦：《S7B/E14 Q&A核心要点与CRO选择策略》《PROARRHYTHMIA模型：从动作电位记录到监管提交》等。 关注北京向新立生物专栏，每周更新，让科学洞察成为你管线最坚固的盾牌。返回搜狐，查看更多

Veteran Biopharma Executive and Venture Investor to Lead Newly Formed Dogwood Advisory Board in advance of Halneuron® Phase 2b Data Which is Projected for Fall of 2026 ALPHARETTA, Ga., June 30, 2026 (GLOBE NEWSWIRE) -- Dogwood Therapeutics, Inc. (Nasdaq: DWTX) (“Dogwood” or the “Company”), a company that focuses on developing first-in-class, new non-opioid medicines to treat pain and neuropathy, today announced the appointment of veteran biopharma industry executive and OrbiMed partner, Iain Dukes, Ph.D., as Chair of the Company’s newly formed Scientific Advisory Board (“SAB”). As Chair of the SAB, Dr. Dukes will advise the Company’s leadership team and Board on scientific developments for the Company’s pipeline of novel therapeutics for pain and neuropathy. Dogwood is currently advancing Halneuron ® in chemotherapy-induced neuropathic pain (“CINP”), with Phase 2b data anticipated in the fall of 2026, and SP16 in chemotherapy-induced peripheral neuropathy (“CIPN”), which has received FDA clearance to progress into Phase 1b development. “Iain is widely recognized throughout the biopharma industry as a successful scientist, investor and business leader, and we are delighted to welcome him as Chair of our newly formed SAB,” said Greg Duncan, Chief Executive Officer of Dogwood Therapeutics. “Dr. Dukes has deep experience in the field of ion channel therapeutics development, and this experience is directly relevant to our ongoing development of Halneuron, a Na V 1.7 sodium channel inhibitor. We look forward to his guidance and expertise as we further expand our SAB and advance our pipeline of novel therapeutics for pain and neuropathy.” Dr. Dukes is a Venture Partner at OrbiMed Advisors LLC. He previously served as Senior Vice President and Head of Business Development and Licensing for Merck Research Laboratories. Prior to joining Merck, Dr. Dukes was Vice President of External Research and Development at Amgen. He has also served as President and Chief Executive Officer, as well as a member of the Board of Directors of Essentialis Therapeutics, a clinical stage biotechnology company focused on the development of breakthrough medicines for the treatment of rare metabolic diseases. Previously, Dr. Dukes was Vice President of Scientific and Technology Licensing at GlaxoSmithKline, and he held various positions at Glaxo Wellcome, including Head of Exploratory Development for Metabolic and Urogenital Diseases and Head of Ion Channel Drug Discovery Group. Dr. Dukes serves on the Board of Directors at Ikena Oncology and Traws Pharma, and privately held biotechnology companies NeRRe Therapeutics, Rathlin Therapeutics, ENYO Pharma, Feldan Therapeutics and Angiex Therapeutics. He holds an M.J. and D.Phil. from the University of Oxford, an M.S. in Cardiovascular Studies from the University of Leeds, and a B.S. in Pharmacology from the University of Bath. About Dogwood Therapeutics Dogwood Therapeutics (Nasdaq: DWTX) is a development-stage biopharmaceutical company focused on developing first-in-class, non-opioid medicines to treat pain and neuropathic disorders. The Dogwood research pipeline includes two first-in-class development candidates, Halneuron and SP16 IV. Our lead product candidate, Halneuron, is in Phase 2b development to treat pain conditions including the neuropathic pain associated with chemotherapy treatment. Halneuron has been granted fast track designation from the FDA for the treatment of CINP. Halneuron is a non-opioid, Na V 1.7 analgesic which is a highly specific voltage-gated sodium channel modulator, a mechanism known to be effective for reducing pain transmission. In clinical studies, Halneuron treatment has demonstrated pain reduction in pain related to general cancer and in pain related to chronic chemotherapy-induced neuropathic pain CINP. SP16 IV is a low-density lipoprotein receptor related protein-1 agonist (“LRP1”) with potential to treat neuropathy and prevent or repair nerve damage following chemotherapy. SP16’s activity as an LRP1 agonist in turn provides alpha-1-antitrypsin-like activity. Consistent with alpha-1-antitrypsin anti-inflammatory and immunomodulatory actions, SP16 preclinically demonstrated anti-inflammatory (analgesic) action via potential reductions in IL-6, IL-8, IL1B and TNF-alpha levels, as well as potential to repair damaged tissue via increases in pAKT and pERK that regulate fundamental processes like growth, proliferation and survival. The forthcoming SP16 IV Phase 1b CIPN trial is fully funded by the National Cancer Institute. Dogwood Therapeutic’s largest shareholder is a member of CK Life Sciences Int’l., (Holdings) Inc., which is listed on the Hong Kong Stock Exchange (Stock code: 0775). For more information, please visit . Forward-Looking Statements: Statements in this press release contain “forward-looking statements,” within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, that are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “suggest,” “target,” “aim,” “should,” "will,” “would,” or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on Dogwood’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict, including risks related to the completion, timing and results of current and future clinical studies relating to Dogwood’s product candidates. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. These and other risks and uncertainties are described more fully in the section titled “Risk Factors” in the most recently filed Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. Forward-looking statements contained in this announcement are made as of this date, and Dogwood undertakes no duty to update such information except as required under applicable law. Investor Relations: Dan Ferry Managing Director LifeSci Advisors, LLC daniel@lifesciadvisors.com