Piromelatine

内华达大学医学院Jeffrey L. Cummings联合克利夫兰诊所、凯斯西储大学医学院，共同总结了2025年阿尔茨海默病（AD）药物研发管线。2025年全年共有182项临床试验评估138种药物；研发管线具有多样性：生物疾病靶向疗法（DTTs）占管线的30%，小分子DTTs占43%；认知增强药物占14%；改善AD患者神经精神症状的药物占11%。生物标志物在其中发挥了重要作用，是27%活跃试验的主要结局指标。再利用药物占管线药物的33%。该综述2025年发表在Alzheimer's & Dementia。  一、数据采集与分析 1.所有数据来源于临床试验注册平台clinicaltrials.gov，该平台由美国国立卫生研究院（NIH）下属的美国国家医学图书馆维护。 2.数据分析解读在内华达大学拉斯维加斯分校临床试验观察站和克利夫兰诊所网络医学实验室进行。 3.索引日期为2025年1月1日。 4.纳排 4.1.包括1期、1/2期、2期、2/3期及3期临床试验；不包含0期或4期临床试验。 4.2.涵盖AD连续谱：临床前AD、MCI/前驱期AD、轻度至重度AD痴呆。 4.3.排除标准： 4.3.1.非药物治疗方案的临床试验，包括运动疗法、生活方式干预、认知行为疗法、照护者干预、膳食补充剂或医用食品等。 4.3.2.干细胞疗法的临床试验亦未纳入。 4.3.3.若无干预措施，则不包含生物标志物相关试验。 5.分析框架： 5.1.基于阿尔茨海默病研究通用本体论（CADRO）对药物靶点进行系统分类，包括：Aβ ；tau蛋白；载脂蛋白E（APOE）、脂质及脂蛋白受体；递质受体；神经发生；炎症；氧化应激；细胞死亡；蛋白质稳态/蛋白病；代谢与生物能量学；血管系统；生长因子与激素；突触可塑性/神经保护；肠-脑轴；昼夜节律；环境因素；表观遗传调控因子；多靶点；未知靶点；其他。 5.2.根据作用机制与靶点信息将药物按治疗目的分类为疾病靶向疗法（DTTs）或对症治疗 5.2.1.“DTT”优于“疾病修饰疗法（DMT）” 5.2.2.将DTTs分为生物制剂（如单克隆抗体、疫苗、反义寡核苷酸[ASOs]）和小分子药物（如通常口服给药且分子量小于500道尔顿的药物）。 5.2.3.将对症治疗药物分为具有潜在认知增强特性的药物和旨在改善神经精神症状（NPS）的药物，明确试验针对的NPS类型如激越、精神病、淡漠。 二、主要结果 1.2025年新药管线概况（原文图1） 1.1.共182项临床试验评估138种AD管线药物 1.1.1.48项评估31种III期药物（原文图3） 1.1.2.86项评估75种II期药物（原文图4） 1.1.3.48项评估45种I期药物。 1.1.4.16/182项是既往试验的长期扩展研究。 1.2.与2024年相比 1.2.1.AD研发管线新增56项临床试验：3期临床试验新增10项，2期新增25项，1期新增21项。 1.2.2.仍在研发管线但现已退出的药物中，25项临床试验已完成，8项终止，8项状态未知（系统中无更新数据）。 1.3.涵盖的AD连续疾病阶段 1.3.1.8项（4%）试验针对认知功能正常但存在症状性AD风险的受试者； 1.3.2.64项（35%）试验纳入被归类为AD或前驱期AD的轻度认知障碍（MCI）患者（无论是否通过生物标志物确认AD病理改变）； 1.3.3.48项（26%）试验涉及早期AD患者（MCI或轻度AD痴呆）； 1.3.4.103项（57%）试验允许轻度AD痴呆患者参与； 1.3.5.75项（41%）试验包含中度或重度AD痴呆患者，以及任何严重程度的AD痴呆患者（这些类别并非互斥，部分试验同时纳入多个类别的受试者）。 1.4.临床试验的地域分布 1.4.1.67项（39%）仅在北美地区开展；47项（28%）仅涵盖北美以外地区； 1.4.2.56项（33%）同时包含北美与非北美地区的临床试验中心（即为“全球性”试验）。 2.基于治疗策略的分类体系 2.1.治疗目的分布: 2.1.1.DTT药物102种（74%）：旨在调控AD病理生理过程，延缓临床衰退 - 42种（30%）生物制剂：如单抗、疫苗、反义寡核苷酸 - 60种（43%）小分子药物：口服，分子量<500道尔顿 2.1.2.对症治疗药物35种（26%） - 认知增强剂：20种（14%） - 神经精神症状（NPS）药物：15种（11%） 2.2.基于 CADRO的靶点分类（原文图2） 2.3.药物种类对应各期临床试验总结如下表 2.4.各阶段在研管线药物靶点汇总如下表 3.生物标志物在2025年阿尔茨海默病（AD）药物研发管线的临床试验中发挥关键作用 3.1.104/182项（57%）临床试验将生物标志物作为入选标准 3.2.影像标志物作为纳排标准 3.2.1.47/182项（26%）使用Aβ—PET作为纳入标准：7项1期试验、29项2期试验和11项3期试验。 3.2.2.59/182项（32%）使用MRI作为排除标准：9项I期试验、32项II期试验和18项III期试验。 3.3.体液标志物 3.3.1.52/182项（29%）使用了体液（包括血液、血浆、血清、脑脊液）标志物作为纳入标准； 3.3.2.17项试验使用了 Aβ 测量指标；17项试验在液体样本中检测了过磷酸化tau蛋白（p-tau）。 3.4.50/182项（27%）以生物标志物作为主要结局指标 3.4.1.26项试验将影像学生物标志物作为主要结局指标，22项试验评估了体液样本。 3.4.2.1项I期试验、4项II期试验和4项III期试验将淀粉样蛋白PET作为结局指标。 3.4.3.MRI作为结局指标的应用包括3项I期试验、4项II期试验和2项III期试验。 3.4.4.作为主要结局指标，11项临床试验评估了 Aβ 变化，其中2项检测了体液样本中的分析物。 3.4.5.测量tau病理学时，1项试验采用tau PET，7项试验使用p-tau生物标志物。 3.4.6.总tau蛋白和神经丝轻链（NfL）分别有2项和3项试验将其作为主要结局指标。 4.联合用药试验：20/182项（11%） 4.1.药效学联合: 10项，靶向炎症或Aβ病理生理学。 - 其中2项采用达沙替尼+槲皮素清除衰老细胞，靶向神经炎症。 4.2.药代动力学联合 4.2.1.10项试验优化药物暴露 4.2.2.6项试验评估右美沙芬与CYP2D6抑制剂的药代动力学组合，旨在降低肝脏代谢、促进活性成分更有效地进入中枢神经系统（CNS）。 4.2.3.4项关于Xanomeline联合trospium的临床试验：阻断外周胆碱能副作用，治疗NPS。 5.2025年预期完成的临床试验 5.1.12种药物完成临床三期：dextromethorphan联合奎尼丁、纳比隆、司美格鲁肽、 simufilam, nilotinib、piromelatine、masupirdine、AR1001、Xanomeline联合trospium、valiltramiprosate、 5.2.Rotigotin联合卡巴拉汀、右美沙芬联合安非他酮。 5.3.29种药物完成临床二期：涵盖神经炎症、tau、突触可塑性等多元靶点。 三、临床意义与结论 1.AD药物研发管线具有较高的活跃度 1.1.Phase 1试验的爆发式增长，增幅约两倍； 1.2.管线多样性（15个CADRO类别）降低了对单一靶点的过度依赖风险。 2.北美地区临床试验点2227个vs全球其他地区2302个试验点，数量大致相当。 2.1.可能加速受试者招募，加速试验进程； 2.2.扩大临床试验队列中受试者的人口统计学特征； 2.3.更深入地理解AD的生物学异质性，提高临床试验结果的普适性，并促进临床实践中精准医疗的实施。 3.生物标志物驱动的范式革命 3.1.影像和血液标志物更多作为药物临床试验的纳排标准和主要结局设定。 3.2.血液生物标志物异军突起 3.2.1.体液标志物已被作为药物开发工具应用于临床试验中的诊断、监测及药效学反应评估。 3.2.2.血液标志物在AD诊断中发挥更大作用。 3.2.3.血浆p-tau217在诊断准确性上与AD病理的脑脊液生物标志物相当。 4.结论 4.1.使用生物标志物来确定资格和作为临床试验的结局指标，显示了生物标志物在阿尔茨海默病药物开发中日益重要的作用。 4.2.生物标志物的发展势头使抗淀粉样蛋白疗法受益，活跃的科学与试验框架可能有助于开发针对更广泛患者群体其他靶点的治疗方案。 4.3.增加临床试验中心数量有助于扩大受试者招募规模，还能提升招募效率、优化运营效能并提高试验质量。 本文仅代表编辑个人对原文献的翻译理解，不能作为直接引用证据。原文献可通过PubMed或杂志官网获取。

iStock/ wildpixel The next generation of Alzheimer’s therapeutics is moving away from amyloid plaques and tau tangles, offering multiple approaches to slow cognitive decline. Over the past two years, Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, both anti-amyloid antibodies, made history as the first real options to slow cognitive decline associated with Alzheimer’s disease. For years, amyloid plaques and tau tangles have been a primary target of Alzheimer’s disease research and drug development, but while affecting these proteins may yield some benefit, the illness continues to progress. Today, multiple therapeutics are in Phase III trials with other targets, suggesting that within the next few years it may become possible to treat Alzheimer’s via multiple pathways. There are currently 32 Alzheimer’s therapeutics in 48 Phase III trials, according to a recent paper by neuroscientist Jeffrey Cummings, a professor at the University of Nevada. Six of those target amyloid-β and one targets tau, but the others aim to affect neuroprotection growth factors, neurotransmitters, neurogenesis, inflammation and proteinopathies. Of those, 21 are meant to be disease-modifying. “Alzheimer’s disease is quite complex in its biology and diagnosis,” Rebecca Edelmayer, vice president of scientific engagement for the Alzheimer’s Association, told BioSpace. “We’re moving to a point where we have better understanding of the disease and what contributes to its symptomology, so those biological underpinnings become targets.” These approaches won’t necessarily replace Leqembi and Kisunla, but they could increase therapeutic options to better manage the disease. The First Anti-Amyloid Antibodies for Alzheimer’s In January 2023, the FDA approved Leqembi as the second disease-modifying treatment for Alzheimer’s disease. The third, Kisunla , followed in July 2024. (The first drug, Eisai and Biogen’s Aduhelm, was discontinued earlier this year.) While Leqembi and Kisunla are a positive step forward, experts suggest there is room for improvement. As measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), Leqembi reduced clinical decline by 27%, whereas Kisunla reduced clinical decline by 29%. In addition to limited efficacy, the drugs both have notable side effects, specifically, the risk of amyloid-related imaging abnormalities (ARIA), the increase in lateral ventricular volume and the simultaneous loss of whole brain volume. A finding of ARIA on imaging tests is indicative of a brain bleed or swelling. When physician online community Sermo questioned 268 neurologists, it found a diversity of opinion on how to best determine clinical benefit. Forty percent of those surveyed have treated Alzheimer’s patients with Leqembi or Kisunla. “There’s debate about whether the two already approved therapeutics are that compelling, so the bar is low,” Andrew Tsai, senior vice president of equity research for the biopharma analyst Jefferies, told BioSpace . A major difference between the two is that Leqembi is infused intravenously twice monthly, while Kisunla is infused only once per month. But any infusion is a pain point for many patients, not to mention a cost to the healthcare system, so easier administration is the goal for several next- gen Alzheimer’s therapeutics. Lilly’s drug is also designed to stop treatment once plaque clearance is achieved. Phase III Alzheimer’s Candidates Athira’s Fosgonimeton Athira Pharma’s fosgonimeton is a small-molecule therapeutic that may be injected daily at home. The company recently reported data from a Phase II/III trial of the drug, which enhances signaling by neurotrophic hepatocyte growth factor (HGF). The trial, which included 315 patients with mild-to-moderate Alzheimer’s disease, failed to meet its primary and key secondary endpoints regarding improvements in cognition and function at the 26-week point. However, pre-specified subgroups experienced rapid disease progression, while both cognition and function either stabilized or improved. Biomarkers also showed improvement, according to the company. In preclinical models of Alzheimer’s disease, fosgonimeton has “been shown to reduce inflammation, improve mitochondrial and synaptic function and reduce amyloid toxicity and p-tau aggregation,” Chief Medical Officer Javier San Martin told BioSpace in an email. “[While] Leqembi and Kisunla are monoclonal antibodies targeting removal of amyloid plaque from the brain with the expectation that by removing amyloid the neurons will be preserved . . . fosgonimeton focuses on improving neuronal health regardless whether the insult is amyloid, tau or other misfolded proteins,” he said. Anavex’s ANAVEX 2-73 In New York, Anavex Life Sciences Corp. is targeting neuronal homeostasis in an ongoing Phase IIb/III study with blarcamesine, an oral, once-daily therapeutic that works “through autophagy through SIGMAR1 activation .” “Blarcamesine’s ability to reduce pathological brain volume loss could be defined as disease-modifying,” Andrew Barwicki, company spokesperson, told BioSpace . In the Phase IIb/III trial , blarcamesine slowed clinical progression of Alzheimer’s by 38.5% at 48 weeks, compared to placebo. Analysis of the Phase IIb/III trial showed no associated neuroimaging adverse events and, unlike Kisunla and Leqembi , blarcamesine is not expected to require routine MRI monitoring. “Blarcamesine could be appealing because of its route of administration and good comparative safety profile,” Barwicki suggested. Anavex anticipates submitting a full regulatory package to the European Medicines Agency by the end of this year. Novo Nordisk’s Semaglutide Novo Nordisk is testing semaglutide , its wildly popular glucagon-like peptide-1 (GLP-1) receptor agonist for weight loss and other indications, in patients with early Alzheimer’s. Completion of the Phase III study is expected in October 2026. Early studies by independent scientists suggest semaglutide reduces neuroinflammation , which impairs cell signaling. It also may improve vascularization. Neurim’s Piromelatine At Neurim Pharmaceuticals, a Phase III trial in Alzheimer’s patients with mild dementia will determine whether piromelatine can improve cognition and function by improving sleep quality. The hypothesis is that sleep disturbances increase synaptic and metabolic activity, impairing the brain’s ability to clear wastes, which then increases amyloid beta aggregation. Piromelatine works by activating certain melatonin and serotonin receptor agonists. Cassava Sciences’ Simufilam Finally, Austin, Texas–based Cassava Sciences seeks to restore the brain’s shape and function by stabilizing the scaffolding protein filamin A (FLNA), thus purportedly blocking signaling from soluble amyloid beta. But Cassava’s conduct around simufilam has spurred an investigation by the U.S. Department of Justice. The company’s former science advisor, Hoau-Yan Wang, was indicted in June for allegedly falsifying scientific data that led to the awards of some $16 million in NIH grants between 2015 and 2023. The charges include allegedly misconstruing data about how “a potential treatment” and its diagnostic test would work. The company’s August corporate overview reiterates a February news release , noting that patients with mild Alzheimer’s who were treated with its oral therapeutic, simufilam , continuously for two years had no decline in their ADAS-Cog scores. Non-continuous treatment resulted in a one-point ADAS-Cog decline. In late July, Cassava added an open-label extension to its ongoing Phase II and III clinical trials for Alzheimer’s, which attracted 89% of its Phase III patients. According to August’s corporate overview, Cassava expects topline results from its 804-patient RETHINK-ALZ trial by year’s end. Combinations Are Key Alzheimer’s is a very hetergeneous disease and there is no magic bullet for treatment. Given the many different mechanisms of action of emerging Alzheimer’s therapeutics, “there may be a case for teaming up and using certain therapeutics in combination,” Tsai said. “We’re excited to see the clinical trial pipeline diversity over time,” Edelmayer added, but the solution may involve more than therapeutics. Ultimately, “Treatment may require a combination of powerful, FDA-approved therapies in conjunction with brain-healthy lifestyles. We envision a future where there are many treatments that address the disease in multiple ways.”