Osugacestat

在早期抗淀粉样蛋白药物陆续获批之后，一批以基因沉默、RNA干预和脑靶向给药技术为代表的“下一代”阿尔茨海默病治疗候选药物正在管线中快速推进，被视为未来可能与现有抗淀粉样抗体形成联合治疗组合的核心力量。 相关研究的进展显示，这些新一代候选药物在作用靶点、给药方式和进入中枢神经系统的能力上均有差异化布局，目标是在减缓疾病进程方面取得比单一机制药物更全面的效果。 近期公开的信息聚焦于四个代表性项目：Biogen 的抗 tau 反义寡核苷酸 BIIB080、Arrowhead 的 ARO-MAPT、Alnylam 的 RNA 干预疗法 mivelsiran，以及 Alector 结合“脑载体”技术的抗淀粉样抗体 AL137。 早期抗淀粉样蛋白药物后的新阶段 阿尔茨海默病药物研发曾长期面临约 99% 的候选失败率，给行业带来显著挫败感。 随着 Biogen 与卫材合作的 Aduhelm、后续的 Leqembi，以及礼来公司的 Kisunla 等抗淀粉样蛋白药物陆续进入市场，研究者获得了在减缓认知衰退方面实现有限但可测量获益的证据。 专家普遍认为，现有抗淀粉样治疗虽然“远非治愈”，但为后续开发多机制组合疗法奠定了重要基础，推动行业从单一靶点迈向更复杂的病理网络干预。 在这一背景下，多家药企开始转向 tau 蛋白、神经炎症与新型给药平台等方向，希望通过更早、更精准的干预提升对疾病进程的调控能力。 业内分析指出，在未来几年内，哪类 tau 靶向或联合机制方案能够与现有抗淀粉样药物最有效地“配对”，将成为决定下一代治疗模式的关键问题之一。 Biogen 的 BIIB080：面向 tau 的反义寡核苷酸 Biogen 在阿尔茨海默病领域仍保持积极布局，其候选药物 BIIB080 是一款针对 tau 蛋白的反义寡核苷酸（ASO），已获得美国 FDA 快速通道资格，目前处于Ⅱ期临床试验阶段。 tau 蛋白是阿尔茨海默病中另一类核心病理蛋白，会在脑内聚集成有毒缠结，被认为与神经元功能损伤密切相关。 BIIB080 通过 ASO 机制在基因表达层面下调 tau 蛋白的产生，有望减少病理性 tau 聚集，从而干预疾病进展。 相较于传统小分子或抗体药物，这类核酸药物的特点在于可直接作用于 RNA 水平，对特定靶基因实现较为精确的表达调控，当前研究重点包括剂量、给药间隔及长期安全性等方面的评估。 Arrowhead 的 ARO-MAPT：靶向 tau 的 RNAi 方案 Arrowhead Pharmaceuticals 推进的 ARO-MAPT 属于 RNA 干预（RNAi）疗法，同样以 tau 相关靶点为核心，被视为下一代基因沉默策略在阿尔茨海默病中的代表之一。 该项目利用短干扰 RNA（siRNA）技术，通过促进靶向 mRNA 的降解来降低病理蛋白表达，从而尝试在早期阶段阻断 tau 相关病理过程。 与 ASO 类似，RNAi 方案在理论上可以长期抑制特定蛋白的生成，但在给药方式、组织分布和持续时间等方面存在差异。 公开信息显示，ARO-MAPT 采用皮下给药的途径，旨在通过系统给药实现对中枢神经系统的有效暴露，这一策略在给药便利性方面具有潜在优势，同时也需要通过临床试验进一步验证其对脑内 tau 水平及认知结局的影响。 Alnylam 的 mivelsiran：同时指向淀粉样与 tau 的 RNAi Alnylam 开发的 mivelsiran 同样是一款 RNAi 疗法，目前在阿尔茨海默病适应证上处于Ⅰ期临床试验阶段。 公司此前披露的计划显示，原本拟于 2025 年第四季度启动Ⅱ期试验，但截至相关报道发布时，该试验尚未在 ClinicalTrials.gov 网站上列出，显示项目仍处于早期推进阶段。 mivelsiran 采用腰椎内注射（鞘内给药）的方式，以便直接进入中枢神经系统，与部分皮下给药 RNAi 产品形成对比。 Alnylam 在阿尔茨海默病领域的布局不仅包括 mivelsiran 这一项目，还在探索另一款针对 tau 的 siRNA 资产 ALN‑5288 等多种机制，以期通过同时针对淀粉样蛋白和 tau 的“上游”基因层面干预，更全面地影响病理蛋白的产生和分布。 公司内部负责人在公开交流中指出，RNAi 途径有望同时作用于细胞内和细胞外两类病理蛋白库，从而在理论上提供比单一靶点抗体更广泛的调控空间，这也是其被视为“下一代”候选的原因之一。 Alector 的 AL137：结合“脑载体”的抗淀粉样抗体 Alector Therapeutics 在早期神经退行性疾病项目上曾遭遇多项临床挫折，但公司在阿尔茨海默病领域并未完全退场，目前除与 GSK 合作的 AL101 外，还在推进一项前期项目 AL137。 AL137 是一款针对淀粉样β（Aβ）的单克隆抗体，但其突出特点在于与公司自研的“脑载体”（Alector Brain Carrier，简称 ABC）技术平台相结合，旨在提升药物穿越血脑屏障的效率。 血脑屏障长期被视为阿尔茨海默病等中枢神经系统疾病治疗的关键难点之一，传统大分子抗体进入脑内的比例极低，需要较高剂量才能达到有效浓度。 Alector 的 ABC 平台基于受体介导转运原理，通过识别脑血管内皮细胞表面的特定受体，实现药物跨越血脑屏障的转运，目标是在降低总体给药剂量的同时提高脑内暴露，进而改善疗效与安全性平衡。 AL137 目前尚处于临床前阶段，其后续进展将取决于毒理学、安全性及非临床药效数据的进一步积累。 组合治疗与未来临床试验方向 当前阿尔茨海默病研究领域逐渐形成共识，即单独依靠抗淀粉样或单一机制药物难以全面改变疾病轨迹，多靶点、多机制的组合治疗很可能成为未来主流路径。 业界观点认为，将抗淀粉样药物与抗 tau、神经炎症调节以及基因层面干预等手段相结合，有望在认知衰退减缓幅度和持续时间上取得叠加效应，这也是 BIIB080、ARO-MAPT、mivelsiran 与 AL137 等候选药物受到关注的重要原因。 在临床试验设计上，越来越多研究开始引入血液和影像等生物标志物，以便更早识别高风险人群并监测药物对病理蛋白水平及脑结构变化的影响。 有研究展望认为，随着血液生物标志物筛查技术的成熟，未来阿尔茨海默病有望在临床症状出现前就进行人群风险识别，并在此基础上开展预防性用药试验，为这些“下一代”候选药物提供更有利的应用场景。 行业观察与后续时间节点 围绕“4 款下一代候选药物”的讨论反映出当前阿尔茨海默病药物研发从单一靶点向多路径并进的转型趋势，重点集中在分子上游干预和脑靶向递送等方向。 未来两到三年内，BIIB080 的Ⅱ期结果、ARO-MAPT 和 mivelsiran 的更长期安全性与药效数据，以及 AL137 从临床前向人体试验的过渡，被视为评估这一“下一代”组合整体潜力的关键时间节点。 在此期间，已有的抗淀粉样抗体及正在推进的其他新药，如正在进行Ⅲ期试验的 remternetug 等，也将持续为临床提供更多关于淀粉样靶点干预的真实世界与试验数据，为未来设计联合用药策略提供参考。 多家研究机构和资助方已在公开渠道强调，将继续支持针对 tau、神经炎症和创新递送技术等方向的项目，以期在现有进展基础上进一步提升阿尔茨海默病治疗的整体效益。 Source： BioSpace: 4 Next-Gen Candidates That Could Form the Future of Alzheimer’s Treatment 关于我们 【未卜先智】是一家专注于人工智能大语言模型在生物医药垂直领域应用的创新公司，我们致力于将前沿的AI技术与专业知识及工作流程深度结合，推动医药产业管理不断向智能化、精准化发展。 如果你对我们的产品感兴趣，欢迎后台联系我们！

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