Trontinemab

点击蓝字 ，关注我们 《柳叶刀-神经病学》（The Lancet Neurology）近期发布的2025年度痴呆诊疗回顾（2025 Round-up）指出，阿尔茨海默病在生物标志物与药物治疗方面实现重要突破，同时其他认知障碍相关领域也在着力构建临床标准与提高诊断准确性。整体来看，2025年的多项进展表明，基于生物学的理解对推动痴呆研究具有关键意义，尤其在诊断、疾病分期和治疗方面 2025年，阿尔茨海默病的生物标志物与药物治疗取得显著进步。新版诊疗指南推荐，对疑似阿尔茨海默病且存在认知障碍的患者，可将血液生物标志物检测纳入整体诊断评估[1]。行为神经病学诊所的真实世界数据证实，阿尔茨海默病的血液生物标志物不仅具有诊断价值，还能指导临床决策。这些标志物常用于复杂病例的诊断，可影响治疗选择，并帮助判断是否需要进行进一步的确诊检测[2]。尽管在常规初级保健中应用血液生物标志物的证据逐渐增多，但如何制定切实可行的实施策略仍是当前的重要课题。 血浆生物标志物p-tau181和p-tau217可用于检测β淀粉样蛋白引起的可溶性Tau蛋白磷酸化变化。最新研究揭示，衰老过程中常见的溶酶体酸度下降会导致此类磷酸化Tau标志物的释放。Tau蛋白的磷酸化会以pH依赖的方式抑制其被蛋白酶切割，这为阿尔茨海默病中磷酸化Tau生物标志物的积累提供了新的机制解释[3]。新近开发的血浆标志物“内源性切割MTBR-tau243（eMTBR-tau243）”能够特异性识别阿尔茨海默病相关的Tau蛋白缠结病理。与其他磷酸化Tau标志物不同，血浆eMTBR-tau243水平与阿尔茨海默病的临床严重程度及Tau蛋白PET分期密切相关[4]。由于检测方便、成本较低，血浆eMTBR-tau243有望成为疾病分期、临床试验受试者筛选或终点评估的重要工具，为Tau蛋白PET成像或脑脊液MTBR-tau243检测提供了替代选择。 除了阿尔茨海默病的诊断进展，其他类型认知障碍疾病的相关领域也在推进临床标准的建立与诊断精度的提升，这些努力为改善临床实践和促进研究带来了希望。例如，边缘系统主导年龄相关性TDP-43脑病（LATE）常与阿尔茨海默病共存，其诊断方法仍需完善。值得关注的是，阿尔茨海默病患者若合并LATE病理，可能影响抗淀粉样蛋白药物的疗效。目前虽已提出LATE的新临床诊断标准，但仍需通过TDP-43特异性生物标志物进一步验证[5]。 在痴呆治疗方面，2025年是具有里程碑意义的一年，抗淀粉样蛋白治疗已在全球范围内进入临床实践。过去一年的证据显示，此类治疗在真实世界临床环境中依然有效，这一点尤其重要，因为临床实践中的患者往往年龄更大、身体更虚弱、认知衰退更严重。一项大型行为神经病学学术实践研究表明，阿尔茨海默病新药仑卡奈单抗（lecanemab）治疗后出现淀粉样蛋白相关影像学异常（amyloid-related imaging abnormalities, ARIA）的发生率与临床症状严重程度有关，凸显了早期干预的重要性[6]。2025年1月，美国食品药品监督管理局（FDA）批准了仑卡奈单抗注射剂型用于阿尔茨海默病，进一步提高了该维持治疗（maintenance therapy）的临床可及性。抗淀粉样蛋白抗体多奈单抗（donanemab）的重要进展在于其滴定方案的优化：从首次输注的700mg中减少350mg，并将这部分剂量加至第三次输注。这一调整使治疗24周时出现淀粉样蛋白相关影像学异常伴脑水肿（ARIA-oedema）的风险从23.7%降至13.7%，其中APOE ε4纯合子患者的风险下降尤为明显。这些发现有望提升治疗可及性并降低不良反应[7]。 在2025年于加拿大多伦多举行的阿尔茨海默病协会国际会议（Alzheimer’s Association International Conference 2025, AAIC 2025）上，研究人员重点介绍了阿尔茨海默病的新兴疗法，其中包括trontinemab的1b/2a期研究的首次数据。trontinemab在28周治疗后实现了淀粉样蛋白清除，且ARIA-oedema发生率保持在5%以下[8]。血脑屏障长期以来是药物递送至中枢神经系统的主要障碍。trontinemab采用Brainshuttle技术递送，其作用机制假说认为可通过转铁蛋白受体介导的胞吞转运，在毛细血管层面完成治疗载体的输送，从而绕过血脑屏障。类似技术也可用于其他治疗药物的递送。 在抗淀粉样蛋白治疗持续发展的同时，针对Tau蛋白清除的新型分子策略不断涌现，包括反义寡核苷酸、亚型特异性Tau抗体以及小干扰RNA等药物。当前临床试验正在关注降低Tau蛋白水平作为治疗靶点的效果，并与抗淀粉样蛋白药物的联合疗法进行对比。阿尔茨海默病Tau蛋白平台试验（注册号NCT06957418和NCT07167966）目前正对处于临床前晚期或前驱期早期的50-80岁成年患者进行研究，评估AADvac1作为单药或与抗淀粉样蛋白单克隆抗体联合使用的疗效。 尽管阿尔茨海默病生物标志物的进展提高了诊断准确性，但新兴疗法的出现也凸显了理解生物标志物与治疗方法之间相互作用的必要性。预计该关键领域在未来一年将持续推进。此外，非药物干预在2025年继续显示其效果。美国POINTER试验表明，对60-79岁具有认知衰退风险的老年人实施结构化、多领域的生活方式干预，可改善整体认知功能[9]。这一发现可能对公共卫生政策具有参考价值。 总体而言，2025年的多项进展彰显了生物学理解在推动痴呆研究中的核心作用，特别是在诊断、分期与治疗方面。这些进展表明，基于生物学的知识框架能够有效引导治疗策略的发展。在阿尔茨海默病领域，疾病修饰疗法不仅通过靶向淀粉样蛋白开辟了新方向，针对Tau蛋白的策略也显示出广阔前景。此外，除阿尔茨海默病外，其他类型痴呆仍需深入探索，以应对持续的疾病挑战并制定有效干预措施。 来源：brainnews 参考文献 [1] Palmqvist S, Whitson HE, Allen LA, et al. Alzheimer’s Association clinical practice guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer’s disease within specialized care settings. Alzheimers Dement 2025; 21: e70535. [2] Prufer Q C Araujo I, Ellingson T, Schwartz NU, et al. Blood-based Alzheimer’s disease biomarkers in a behavioral neurology clinic: real-world implementation, clinical utility, and diagnostic performance. Alzheimers Dement 2025; 21: e70891. [3] Lane-Donovan C, Smith AW, Saloner R, Miller BL, Casaletto KB, Kao AW. Tau phosphorylation at Alzheimer’s disease biomarker sites impairs its cleavage by lysosomal proteases. Alzheimers Dement 2025; 21: e70320. [4] Horie K, Salvadó G, Koppisetti RK, et al. Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease. Nat Med 2025; 31: 2044–53. [5] Wolk DA, Nelson PT, Apostolova L, et al. Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy. Alzheimers Dement 2025; 21: e14202. [6] Paczynski M, Hofmann A, Posey Z, et al. Lecanemab treatment in a specialty memory clinic. JAMA Neurol 2025; 82: 655–65. [7] Wang H, Serap Monkul Nery E, Ardayfio P, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement 2025; 21: e70062. [8] Smith J, Mummery C, Cummings JL, et al. TRONTIER 1 and TRONTIER 2: pivotal trials of trontinemab in early symptomatic Alzheimer’s disease. Alzheimer’s Association International Conference, July 27–31, 2025. [9] Baker LD, Espeland MA, Whitmer RA, et al. Structured vs self-guided multidomain lifestyle interventions for global cognitive function: the US POINTER randomized clinical trial. JAMA 2025; 334: 681–91. 威斯金医学 WESKIN 重庆威斯金医学检验实验室有限公司（简称“威斯金医学”）旨在建立西南地区首家以“脑神经退行性疾病早期精准检测”为特色的高端精准医学中心，公司组建了以国际领先水平的全自动免疫分析技术、多基因PCR array芯片技术、高灵敏度微流控多靶标检测技术、基因编辑及AI分析技术为核心技术的临床免疫实验室，集脑神经退行性疾病创新诊断技术研究、阿尔茨海默病生物标志物试剂开发、创新成果转化及第三方医学检验服务于一体，实行“国际领先高端检测技术引进+自主知识产权创新技术自研”并举的发展策略，致力打造国际化、标准化高端临床检测平台，推动临床脑神经退行性疾病精准诊断市场的合规化与标准化。 公司以“一中心+两基地”的模式，在重庆脑与智能科学中心、重庆生物医药研发产业园、北京大兴设有完善的研发基地以及IVD万级净化生产基地以及阿尔兹海默症（AD）新药开发研究基地，依托AD药物开发模型工具，致力于AD新药的研究与开发，推动AD诊疗领域的发展。公司现已与多家医院建立良好的合作关系，致力于推动个性化精准医学临床诊断技术的创新与应用，助力医疗卫生事业的发展。 威斯金医学以创新为驱动，通过自主创新和产学研合作，不断攻克“卡脖子”医检技术，催生新技术和新产品应用于脑神经退行性疾病及肿瘤等重大疾病的早期筛查、精准检测、辅助治疗、预后监测等环节，助力精准医学检测技术的全面落地及普及，造福更多患者，为“健康中国”战略的实现贡献力量，为医疗行业的发展注入新的活力和动力。 往期回顾 JAMA｜Tau-临床不匹配个体中共病理和临床进展轨迹的评估 Brain｜浙大沈逸/周煜东团队揭示星形胶质细胞参与阿尔茨海默病早期发病的新机制 Cell｜袁钧瑛/邹呈雨等阐述Treg研究荣获诺奖后的下一步研究重点与挑战 威斯金医学 询恰热线丨400-661-5168 版权声明：除原创内容及特别说明之外，推送稿件部分文字及图片均来自网络及主流媒体。如认为有侵权内容，请联系我们删除。 END

iStock, wildpixel Following the hard-won success of early anti-amyloid drugs, a new generation of Alzheimer’s modalities—from tau-targeting gene silencers to blood-brain barrier delivery platforms—is entering the pipeline to anchor future combination therapies. The development of treatments for Alzheimer’s disease has been marked by consistent disappointment, with a demoralizing 99% candidate failure rate . However, recent market entrants—beginning with Biogen and Eisai’s ill-fated Aduhelm , then their more prosperous Leqembi and Eli Lilly’s Kisunla —have defied these odds. With proof that progress is possible in this space, a new wave of treatments has emerged in the early-stage pipeline. Many of these candidates are taking novel approaches to the disease, whether through gene silencing, antisense platforms or improved drug-delivery technologies. Having various modalities with different targets coming through the pipeline could be especially important as the treatment landscape matures, with a combination of approaches likely to be key to managing Alzheimer’s disease, Patrick Trucchio, managing director of Equity Research at H.C. Wainwright, told BioSpace . Several companies, including Eisai, Bristol Myers Squibb and Merck, are working on another common Alzheimer’s target: the tau protein. “KOLs . . . expect it will take a combination of anti-amyloid, anti-tau and then some sort of neuroinflammatory drug to address the disease,” he said. “In terms of tau-targeting, I think the next two years will determine which candidates and which type of approach is going to be paired with the amyloid drugs.” Against this backdrop, attention is turning to the next generation of Alzheimer’s drugs that could form the backbone of future combination therapies. Alzheimer’s disease Eisai Still Confident in Anti-Tau Asset as J&J Becomes Latest Victim in Spiraling Space Days after Johnson & Johnson’s posdinemab failed to slow clinical decline in patients with Alzheimer’s disease, Eisai Chief Clinical Officer Lynn Kramer expressed unwavering conviction in his company’s own anti-tau asset, while others suggest the Alzheimer’s field is heading in a completely different direction. December 5, 2025 · 4 min read · Heather McKenzie Biogen’s BIIB080 Antisense oligonucleotide Biogen was there in the beginning, and the company remains in the thick of the next generation of Alzheimer’s R&D. BIIB080, a tau-targeting antisense oligonucleotide (ASO) granted FDA Fast Track designation last year, is currently being evaluated in Phase II trials. A popular target, the tau protein forms into toxic tangles in the brains of individuals living with Alzheimer’s. Phase Ib data presented at the International Conference on Alzheimer’s and Parkinson’s Diseases in 2023 showed BIIB080 reduced soluble tau protein in cerebrospinal fluid (CSF) in patients with early-stage Alzheimer’s. The clinical study was the first to show a reduction of this magnitude in tau PET across brain regions, Biogen said in its press release at the time. The ASO therapy reduced biomarkers of tau in all dose groups by approximately 60% compared to baseline. Biogen announced in April 2025 that the Phase II CELIA trial of BIIB080 was fully enrolled. The study’s completion date is set for May , with readouts expected this year. This readout will be one of the most significant for Alzheimer’s in 2026, Laura Nisenbaum, executive director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace . “So far, the drug appears to be safe and to reduce tau levels in the brain,” she said. “What we’re looking to see next is whether this holds across more individuals, continues to be safe and possibly has an impact on cognitive symptoms.” Arrowhead Pharmaceuticals’ ARO-MAPT RNA interference therapy California-based Arrowhead is also working on a tau-targeting asset, an investigational RNA interference therapeutic called ARO-MAPT. Arrowhead launched a Phase I/IIa trial of the treatment in Alzheimer’s and other tauopathies last month. Traditional methods of targeting tau, such as antibodies and small molecules, have had difficulty in modulating the protein, which makes it ideal for a siRNA-mediated knockdown approach, James Hamilton, chief medical officer at Arrowhead, told BioSpace in an email. The primary reason for the other approaches’ struggles, Hamilton said, is that “tau monoclonals do not adequately target intracellular tau neurofibrillary tangles, which are one of the key drivers of disease biology.” ARO-MAPT, on the other hand, “targets tau mRNA expression in neurons and is administered by a subcutaneous injection,” he explained. Arrowhead is hoping its study will show reductions in CSF translating into lower levels of regional brain tau, Hamilton said. He noted that the study will also include cognitive measures and other disease-relevant rating scales but cautioned that the trial is likely too small to show an effect on cognition, with this set to be assessed in Phase II trials. The company is anticipating initial data from the first parts of the study in the second half of this year, Hamilton said in the December press release announcing the trial’s launch. With Arrowhead’s and other significant readouts expected this year, Trucchio referred to 2026 as “the year of tau,” adding that 2027 will also be crucial. The data from these trials will be important because they will help confirm the most appropriate approach, Trucchio said, likening the different methods of tau reduction to either “a chisel or a sledgehammer.” Weight Loss Arrowhead Enters Obesity Chat by Doubling Tirzepatide’s Weight Loss in Combo Study Arrowhead heralded the results as proof of concept that inhibiting the Activin E pathway can improve body composition and enhance weight loss as compared to tirzepatide alone, particularly in patients with type 2 diabetes. January 6, 2026 · 3 min read · Annalee Armstrong Alnylam’s Mivelsiran RNA interference therapy Alnylam’s mivelsiran, also an siRNA therapy, is being tested in Phase I trials for Alzheimer’s disease. Plans were underway to initiate a Phase II trial during the fourth quarter of 2025, according to the biotech’s third-quarter 2025 earnings report , but as of publication no such trial was listed on ClinicalTrials.gov . While part of the same class as ARO-MAPT, mivelsiran is delivered via intrathecal rather than subcutaneous injection. Alnylam is targeting amyloid in its Phase I trial, while a further asset, ALN-5288, also a siRNA, is being explored to target tau. “With RNAi, we can target amyloid-beta and tau at their genetic source, addressing both intracellular and extracellular pools of these problematic proteins,” Tim Mooney, program lead for mivelsiran at Alnylam, told BioSpace in an email. “This upstream approach may be able to more comprehensively address drivers of Alzheimer’s progression compared to other modalities.” Echoing Trucchio, Mooney said Alnylam expects the future of Alzheimer’s treatment to comprise a variety of approaches and combinations to provide “a more comprehensive effect.” This includes looking at approaches that extend beyond targeting amyloid and/or tau proteins, he added, with Alnylam “exploring multiple mechanisms” to address the disease. “Looking further into the future, we anticipate that diagnostic screening with blood-based biomarkers may eventually play a role in helping to identify individuals at risk of developing AD who could benefit from treatment with targeted therapeutic approaches like ours to prevent the onset of dementia altogether,” Mooney said. Alector Therapeutics’ AL137 Next-gen antibody paired with brain carrier technology Alector suffered two setbacks to its neurodegenerative pipeline, experiencing clinical trial failures in its partnerships with both AbbVie and GSK in a 13-month span. The biotech is still developing AL101 alongside GSK for Alzheimer’s but has pivoted its approach in its earlier-stage pipeline. AL137, a preclinical anti-amyloid beta antibody, is being paired with Alector’s “brain carrier” (ABC) delivery technology to target Alzheimer’s disease. This design is intended to counter one of the major barriers to administering treatments for Alzheimer’s by navigating the blood-brain barrier (BBB). Alector’s ABC technology uses receptor-mediated transcytosis to cross the BBB, targeting specific receptors of endothelial cells to facilitate the delivery of therapeutics. This delivery technology is designed to improve drug delivery and also to reduce dose levels whilst maintaining efficacy, according to the company’s website. Navigating the BBB could help to prevent one of the key known side effects of the anti-amyloid antibody class: amyloid-related imaging abnormalities (ARIA), Trucchio said. Last July, Lilly’s Kisunla received a label update for its dosing schedule to reduce the likelihood of ARIA. ARIA prevention is now becoming a key differentiator that companies in this space hope to achieve, Trucchio said, adding that analysts will be looking to the next-generation anti-amyloid therapies or delivery platforms to deliver this. As the potential for improved delivery of Alzheimer’s treatments becomes clear, companies emerging later into the space—or those on the rebound, such as Roche with its antibody trontinemab —are leveraging this as a means to catch up to the early frontrunners. The progress currently being seen in the Alzheimer’s space is lifting the negativity that existed in the field five years ago, Nisenbaum said. “With the success of anti-amyloid therapies and the development and approval of blood-based biomarker tests, we’ve seen renewed excitement and a greater willingness from drug developers to enter this space.” Neuropsychiatric disorders Alector Scraps Dementia Drug After Phase III Flop, Lays Off 49% of Staff This represents Alector’s second failed neurodegenerative asset in a year, after an AbbVie-partnered asset missed in Alzheimer’s last November. On latozinemab for frontotemporal dementia, Alector was working with GSK, which fronted $700 million in 2021 to collaborate on two programs. October 22, 2025 · 2 min read · Tristan Manalac