A Window-of-opportunity Early Phase I Randomized Study of Neoadjuvant Chemoradiotherapy With or Without Concurrent Azeliragon in Patients With Newly Diagnosed Glioblastoma

Preclinical data have demonstrated the combination of azeliragon, a RAGE inhibitor, with radiation therapy (RT) can effectively reduce immune-suppressive myeloid cells and restore T-cell activation to improve tumor control in murine glioma models. Ongoing clinical studies of azeliragon with RT alone and RT plus temozolomide (TMZ) to treat patients with newly diagnosed glioblastoma (GBM) have demonstrated safety and tolerability. The purpose of this window-of-opportunity study is to validate that the combination of azeliragon with RT and TMZ would modulate immune-suppressive myeloid and T cells in the tumor microenvironment in patients with GBM.

开始日期2025-11-06

申办/合作机构

Washington University School of Medicine

[+1]

NCT06724926

/ Recruiting临床1期IIT

A Phase IB Study to Assess Safety of Concurrent Azeliragon With Craniospinal Irradiation in Patients With Leptomeningeal Metastasis From Solid Tumor Malignancies or High-Grade Gliomas

Single institution study to assess the safety of concurrent Azeliragon with craniospinal irradiation (CSI) in patients with leptomeningeal metastasis from solid tumor malignancies and high-grade gliomas.

开始日期2025-02-19

申办/合作机构

NYU Langone Health

NCT05773664

/ Withdrawn临床1期IIT

A Phase I De-Escalation Study of Dexamethasone with Azeliragon for Management of Post-Resection Cerebral Edema in Patients with Glioblastoma

This phase I trial tests the safety, side effects, and best dose of dexamethasone when given with azeliragon in managing cerebral edema after surgery (post-resection) in patients with glioblastoma. Cerebral edema is a pathological increase in the water mass contained within the brain interstitial space. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Azeliragon is an oral RAGE inhibitor. Blocking the RAGE pathway at the time of surgery (peri-operatively) may decrease cerebral edema. Giving dexamethasone with azeliragon may help control post-operative cerebral edema in decreasing doses of concurrently administered dexamethasone.

开始日期2024-11-15

申办/合作机构

City of Hope National Medical Center

[+1]

100 项与 Azeliragon 相关的临床结果

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100 项与 Azeliragon 相关的转化医学

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100 项与 Azeliragon 相关的专利（医药）

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项与 Azeliragon 相关的文献（医药）

2025-12-01·AGEING RESEARCH REVIEWS

Unravelling neuronal death mechanisms: The role of cytokines and chemokines in immune imbalance in Alzheimer’s disease progression

Review

作者: Sharma, Prajjwal ; HariKrishnaReddy, Dibbanti ; Medhi, Bikash ; Vellingiri, Balachandar ; Paidlewar, Mohit ; Dhapola, Rishika ; Kumari, Sneha

Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of inflammatory mediators contributes to or results from amyloid-β and tangle deposition, triggers oxidative stress, excitotoxicity, and neuroinflammation, leads to cell death through multiple mechanisms, including apoptosis, ferroptosis, pyroptosis, PANoptosis, etc. The pathogenetic mechanisms responsible for neuronal death and dysfunction in AD are not yet fully understood. This review seeks to compile evidence for the various modes of neuronal cell death in AD and to explore how the neuroinflammatory environment of the AD brain influences these distinct forms of cell death. Several inflammatory signalling cascades are involved in above discussed neuronal death mechanisms, such as RAGE/NF-κB, NLRP3 inflammasome, AMPK/mTOR/ULK1, cGAS-STING, RIPK1/RIPK3/MLKL, GPX4/Nrf2 and JAK-STAT pathways. Therapeutic drugs such as Magnolol, Necrostatin-1, Salidroside, Azeliragon, DNL788, Baricitinib, Sargramostim, etc. targeting neuroinflammation-associated signaling pathways, have shown efficacy in preclinical and clinical studies mitigating AD pathology. Enhancing our comprehension of neuronal death mechanisms could elucidate disease pathogenesis, offer insights for therapeutic approaches, and aid in developing modified animal models of AD.

2025-12-01·BRAIN RESEARCH

RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications

Review

作者: Goda, Jayant S ; Chatterjee, Abhishek ; Shah, Janmay ; Ande, Deepak ; Ghanekar, Shubham ; Raj, Jemema Agnes Tripena ; John, Geofrey ; Thiruselvan, Gokula Krishnan

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with standard therapies offering only modest survival benefits. A major challenge in its management is radiation therapy (RT), which, while indispensable for tumor control, often damages normal brain tissue and contributes to radiation-induced cognitive decline (RICD). This dual burden of tumor progression and treatment-associated neurotoxicity underscores the need for molecular targets that link oncogenesis and neuroinflammation. The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor activated by HMGB1, S100 proteins, and advanced glycation end-products (AGEs), all of which are elevated in both GBM and irradiated tissues. RAGE signaling engages NF-κB, JAK/STAT, and MAPK pathways, driving glioma cell migration, angiogenesis, and immune evasion while amplifying oxidative stress and chronic neuroinflammation in the surrounding parenchyma. These effects not only promote tumor progression and resistance to RT but also impair synaptic plasticity and cognitive function, paralleling mechanisms seen in neurodegenerative disease. Therapeutically, targeting RAGE represents a dual opportunity: suppressing GBM aggressiveness while mitigating RICD. Small-molecule inhibitors such as FPS-ZM1 and Azeliragon, biologics including sRAGE and RAGE antagonistic peptides, and phytochemicals such as curcumin, Tanshinone IIA, and berberine demonstrate the feasibility of modulating this pathway in preclinical models. Collectively, the evidence highlights the RAGE signaling as one of the central modulators of GBM progression and RT-induced cognitive decline through NF-κB, JAK/STAT, and MAPK activation. Future strategies that selectively disrupt pathological RAGE signaling, while sparing physiological functions, may provide transformative therapeutic avenues for patients facing the dual burden of glioblastoma and radiation-induced neurotoxicity.

2025-06-09·INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

RAGE Is Essential for Subretinal Fibrosis in Laser-Induced Choroidal Neovascularization: Therapeutic Implications

Article

作者: Sreekumar, Parameswaran G. ; Hong, Elise ; Kannan, Ram ; Nagaraj, Ram H. ; Nam, Mi-Hyun

Purpose:

Subretinal fibrosis, a complication of neovascular age-related macular degeneration (nAMD), involves the epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells as a contributing mechanism. The receptor for advanced glycation end products (RAGE) is a multiligand receptor implicated in fibrotic diseases, but its role in subretinal fibrosis has not been studied. This study investigated the role of RAGE in subretinal fibrosis.

Methods:

Subretinal fibrosis was induced in male RAGE-/- and wild-type (WT) mice via laser photocoagulation, and fibrosis lesion volume was assessed on day 35 using optical coherence tomography and immunostaining. In vitro, EMT was induced in primary human RPE cells with transforming growth factor-beta 2 (TGF-β2). The role of RAGE in EMT was studied in cells pretreated with RAGE antagonists (FPS-ZM1 or azeliragon), followed by cotreatment with TGF-β2 for 48 hours. Signaling studies were conducted by pretreatment with FPS-ZM1 for 2 hours, cotreatment with TGF-β2 for 60 minutes, and subsequent immunoblot analysis.

Results:

In RAGE-/- mice, subretinal fibrosis after laser-induced choroidal neovascularization was significantly reduced, with a smaller fibrosis volume, less inflammation, decreased activation of pSmad2, and reduced deposition of fibrotic markers (αSMA, collagen I) compared to WT mice. In vitro treatment with TGF-β2 in human RPE cells increased mitochondrial reactive oxygen species and upregulated EMT markers (αSMA, collagen I, and fibronectin), which were inhibited by cotreatment with FPS-ZM1 or azeliragon. FPS-ZM1 blocked TGF-β2-induced Smad2-dependent signaling and EMT without affecting the extracellular signal-regulated kinase (ERK) pathway.

Conclusions:

Our findings indicate that RAGE plays a role in RPE cell EMT in subretinal fibrosis and that RAGE antagonists attenuate this process, making RAGE a promising therapeutic target for subretinal fibrosis in nAMD.

项与 Azeliragon 相关的新闻（医药）

2025-11-25

·阿尔茨海默病研究

阿尔茨海默病的药物治疗:现状与未来

Claude Sonnet 4.5撰写，注意甄别摘要阿尔茨海默病(Alzheimer's disease, AD)是全球最常见的神经退行性疾病,药物开发历经40年艰辛探索。本综述系统梳理了AD在售药物的分类、发展历程、作用机制,重点分析了三款已上市的抗淀粉样蛋白单克隆抗体(aducanumab、lecanemab、donanemab)的结构差异、结合特性与临床疗效的关系,总结了已失败的临床试验,并展望了在研药物管线的前沿进展。1. 小分子药物:按治疗路径分类与发展时间线1.1 药物分类列表表1. 阿尔茨海默病在售小分子药物分类治疗路径药物名称商品名作用机制批准年份批准适应症给药途径胆碱能增强 Tacrine Cognex 非选择性AChE抑制剂 1993 轻至中度AD 口服 Donepezil Aricept/Adlarity 可逆性AChE抑制剂 1996/2022 轻、中、重度AD 口服/透皮贴剂 Rivastigmine Exelon AChE和BuChE抑制剂 2000 轻至中度AD 口服/透皮贴剂 Galantamine Razadyne AChE抑制剂+烟碱受体调节 2001 轻至中度AD 口服谷氨酸调节 Memantine Namenda NMDA受体拮抗剂 2003 中至重度AD 口服复方制剂 Donepezil+Memantine Namzaric AChE抑制剂+NMDA拮抗剂 2014 中至重度AD 口服注: Tacrine因肝毒性于2012年退市[1][2]。1.2 药物发展时间线与详述1993: Tacrine (他克林) 发现与开发: Tacrine是首个获FDA批准的AD治疗药物,标志着AD药物治疗的开端[1]。它于1986年开始临床试验,1993年9月9日获批用于轻至中度AD[2]。Tacrine是一种非选择性胆碱酯酶抑制剂,可同时抑制乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)[3]。作用机制: 通过抑制AChE降解乙酰胆碱,增加突触间隙乙酰胆碱浓度,改善胆碱能神经传递[4]。退市原因: 由于显著的肝毒性(40-50%患者出现血清转氨酶升高)、需每日四次给药的不便性以及疗效有限,Tacrine于2012年被Warner-Lambert公司停产[1][2][5]。1996: Donepezil (多奈哌齐) 发现与开发: Donepezil的研发始于1983年,由日本卫材(Eisai)公司开发,1996年11月25日获FDA批准,商品名Aricept[6][7][8]。它是tacrine退市后AD治疗的主导药物,至今仍是全球处方量最大的AD药物[9]。2022年,透皮贴剂剂型(Adlarity)获批,改善了给药依从性[10]。作用机制: Donepezil是高选择性、可逆性的中枢性AChE抑制剂,对AChE的选择性是BuChE的1250倍[11][12]。其半衰期长达70小时,允许每日一次给药[13]。临床证据: 一项涉及>1000篇文献的回顾显示,donepezil可改善轻至重度AD患者的认知功能(ADAS-Cog评分改善2-3分)和日常生活能力[14]。网络meta分析表明,donepezil在认知改善方面显示最高疗效水平[15]。药物基因组学: CYP2D6和CYP3A4基因多态性影响donepezil代谢,但尚未在临床常规应用[14]。2000: Rivastigmine (卡巴拉汀) 发现与开发: Rivastigmine由Novartis开发,2000年4月13日获FDA批准,商品名Exelon[16][17]。它是首个获批用于轻至中度AD的双重胆碱酯酶抑制剂[18]。透皮贴剂剂型于2007年获批,显著降低了胃肠道副作用[19]。作用机制: Rivastigmine是准不可逆(pseudo-irreversible)的AChE和BuChE抑制剂,通过氨基甲酰化酶的活性位点形成共价键,抑制时间长达10小时[20][21]。其独特之处在于同时抑制两种胆碱酯酶,理论上可提供更广泛的胆碱能增强[22]。临床证据: 在轻至中度AD患者中,rivastigmine可改善认知功能和日常生活能力,疗效与donepezil相当[23]。透皮贴剂显示出更好的耐受性,胃肠道副作用发生率降低50%[24]。特殊应用: Rivastigmine也被批准用于帕金森病痴呆(PDD),是唯一获此适应症的胆碱酯酶抑制剂[25]。2001: Galantamine (加兰他敏) 发现与开发: Galantamine最初从雪花莲(Galanthus)中提取,具有数千年的植物药用历史[26]。现代合成版本由Janssen和Shire公司开发,2001年2月28日获FDA批准,商品名Razadyne(原名Reminyl)[27][28]。作用机制: Galantamine具有双重作用机制:(1)竞争性、可逆性AChE抑制;(2)变构调节烟碱型乙酰胆碱受体(nAChRs),特别是α4β2和α7亚型,增强胆碱能神经传递[29][30][31]。这种独特的烟碱受体调节作用理论上可提供神经保护效应[32]。临床证据: 在轻至中度AD患者中,galantamine显示出与donepezil相当的认知改善效果[15]。网络meta分析显示galantamine在认知功能改善方面排名第一或第二[15][33]。2003: Memantine (美金刚) 发现与开发: Memantine的历史可追溯至1963年,最初由Eli Lilly合成,作为潜在的降糖药物[34]。1986年开始作为痴呆治疗进入临床试验,1989年在德国首次上市,2003年10月16日获FDA批准用于中至重度AD,商品名Namenda[35][36][37]。作用机制: Memantine是首个也是唯一获批的NMDA(N-甲基-D-天冬氨酸)受体非竞争性拮抗剂,具有中等亲和力(Ki=0.5μM)和快速解离动力学[38][39]。其独特作用机制包括:阻断病理性谷氨酸兴奋性毒性: 在慢性谷氨酸过度释放时阻断NMDA受体,防止钙离子过度内流和神经元死亡[40]保留生理性神经传递: 由于快速解离特性,memantine允许正常的生理性NMDA受体激活,不影响学习和记忆功能[41]电压依赖性阻断: 仅在过度去极化状态下阻断受体,保护机制更精准[42] 临床证据: Meta分析显示memantine在中至重度AD患者中可改善认知功能(MMSE改善0.99分)、整体功能和日常生活能力[43][44]。与胆碱酯酶抑制剂联合使用可能产生协同效应[45]。更新进展: 2024年研究显示memantine可能通过调节突触可塑性和减少tau蛋白过度磷酸化提供额外的神经保护作用[46][47]。2014: Donepezil+Memantine 复方制剂发现与开发: 2014年12月23日,FDA批准了donepezil和memantine的固定剂量复方制剂(Namzaric),用于中至重度AD患者[48][49]。这是首个结合胆碱能增强和谷氨酸调节的复方制剂。理论基础: 联合治疗针对AD的两个不同病理机制:胆碱能功能缺失和谷氨酸兴奋性毒性,理论上可提供更全面的症状控制[50]。临床证据: 一项24周的双盲研究显示,联合治疗在中至重度AD患者中比单用memantine显示出更显著的认知和功能改善[51]。长期研究(52周)显示联合治疗延缓了认知衰退和功能恶化[52]。1.3 小分子药物的局限性尽管这些小分子药物已使用20-30年,但它们仅提供症状性治疗,不能改变疾病进程[53][54]。Meta分析显示,胆碱酯酶抑制剂的平均疗效仅为2-3个ADAS-Cog评分点,临床意义有限[55][56]。此外,约30-50%患者因胃肠道副作用(恶心、呕吐、腹泻)而停药[57]。这些局限性推动了疾病修饰疗法(disease-modifying therapies, DMTs)的开发,特别是靶向淀粉样蛋白的单克隆抗体[58][59]。2. 靶向Aβ的单克隆抗体:三款上市药物的深度分析2.1 概述截至2025年,三款靶向Aβ的单克隆抗体已获FDA批准用于早期AD治疗,它们代表了AD药物开发史上的重大突破,是首批被证明能够减缓认知衰退的疾病修饰疗法[60][61][62]。表2. 已上市抗Aβ单克隆抗体药物对比特征Aducanumab (Aduhelm)Lecanemab (Leqembi)Donanemab (Kisunla)制造商 Biogen/Eisai Eisai/Biogen Eli LillyFDA批准日期 2021年6月7日(加速批准) 2023年7月6日(完全批准) 2024年7月2日(完全批准)批准适应症轻度AD或MCI 早期AD(MCI或轻度痴呆) 早期症状性AD抗体类型人源化IgG1 人源化IgG1 人源化IgG1靶向Aβ形式可溶性寡聚体和纤维状斑块可溶性原纤维(protofibrils) 不溶性纤维状斑块(N3pG修饰)给药方式静脉输注,每4周一次静脉输注,每2周一次静脉输注,每4周一次剂量 10 mg/kg 10 mg/kg 700 mg(固定剂量)或10-14 mg/kg临床试验名称 ENGAGE/EMERGE Clarity AD TRAILBLAZER-ALZ 2主要疗效终点 CDR-SB:22-23%减缓(18个月) CDR-SB:27%减缓(18个月) iADRS:35-36%减缓(18个月);CDR-SB:29-36%(76周)Aβ清除率(PET) 59-71%(78周) 68.1%(18个月) 84.8%(76周)ARIA-E发生率 35.2%(高剂量组) 12.6% 24.0%ARIA-H发生率 19.1% 17.3% 31.4%市场状态 2024年11月停产在售在售2.2 Aducanumab (Aduhelm):首个获批但争议最大2.2.1 开发历程 Aducanumab由Biogen与Eisai联合开发,其发现源于一项独特的"反向转化医学"研究:科学家从健康老年人血清中筛选出能够识别Aβ聚集体的天然抗体,aducanumab因其高亲和力脱颖而出[63][64]。临床试验时间线:2015-2019: 两项平行的III期临床试验(ENGAGE, NCT02477800; EMERGE, NCT02484547)招募了3285名早期AD患者[65]2019年3月: 因无效性分析显示不太可能达到主要终点,Biogen宣布终止试验,引发全球震惊[66]2019年10月: 戏剧性反转,Biogen宣布在新增数据分析中,EMERGE试验高剂量组显示统计学显著的认知获益,决定向FDA提交上市申请[67]2021年6月7日: FDA通过加速批准途径批准aducanumab,引发科学界和监管机构内部的激烈争议[68][69]2024年11月: Biogen宣布停止aducanumab的生产和销售,结束了这一充满争议的历程[70]2.2.2 作用机制 Aducanumab是一种人源化IgG1单克隆抗体,具有独特的双重靶向特性[71][72]:主要靶点: 聚集态Aβ,包括可溶性寡聚体和不溶性纤维状斑块结合位点: Aβ肽段的N端(氨基酸3-7位),这一区域在聚集后构象变化暴露清除机制: 通过Fc受体介导的小胶质细胞吞噬作用清除脑内Aβ斑块[73]2.2.3 临床数据 EMERGE试验(阳性试验): 高剂量组(10 mg/kg)在18个月时CDR-SB评分减缓23%(p=0.01)[74] MMSE评分改善15%(p=0.04) ADAS-Cog13改善27%(p=0.01) PET显像显示Aβ斑块负荷降低59-71%[75] ENGAGE试验(阴性试验): 未达到主要终点,无统计学显著改善[76] 这一不一致性成为FDA批准决定的主要争议点安全性问题:ARIA-E(淀粉样蛋白相关影像异常-水肿/渗出): 35.2%[77]ARIA-H(微出血/含铁血黄素沉积): 19.1%[78] APOE ε4携带者ARIA风险显著增加(纯合子>50%)[79]2.2.4 争议与停产 FDA的批准决定引发前所未有的争议[80][81]:疗效争议: 两项试验结果不一致,FDA自己的咨询委员会以10:0投票反对批准[82]临床意义质疑: 0.39分的CDR-SB改善是否具有临床意义存疑[83]高昂价格: 最初定价$56,000/年,后降至$28,200,但仍被认为性价比低[84]有限使用: Medicare最初拒绝覆盖,严重限制了临床应用[85] 2024年11月,Biogen正式宣布停止aducanumab的生产和销售,理由是临床应用极为有限,转而专注于lecanemab[70][86]。2.3 Lecanemab (Leqembi):当前的金标准2.3.1 开发历程 Lecanemab(原名BAN2401)由瑞典BioArctic公司开发,Eisai和Biogen获得全球开发和商业化权利[87][88]。其设计基于对Aβ聚集级联的深入理解,特异性靶向早期毒性形式的Aβ。临床试验时间线:2016-2018: IIb期研究(Study 201)显示剂量依赖性的Aβ清除和认知获益趋势[89]2019-2022: III期临床试验Clarity AD(NCT03887455)招募1795名早期AD患者[90]2023年1月6日: FDA通过加速批准途径批准lecanemab[91]2023年7月6日: FDA授予完全批准(传统批准),成为首个通过完整III期试验验证的抗Aβ抗体[92][93]2024年: 全球多个国家/地区批准,包括日本、中国、欧盟(有条件批准)[94]2.3.2 作用机制 Lecanemab具有高度特异性的靶向特性,这是其安全性和疗效优势的关键[95][96]:主要靶点: 可溶性Aβ原纤维(protofibrils),这是介于单体和成熟纤维斑块之间的中间聚集形式,被认为是最具神经毒性的Aβ形式[97][98]结合特性: 对原纤维的亲和力比单体高1000倍以上,比成熟纤维高10-100倍[99]结合位点: Aβ肽段的中段和C端区域清除机制: (1)直接中和可溶性原纤维的毒性;(2)通过小胶质细胞介导的吞噬作用清除;(3)可能阻止原纤维向成熟斑块转化[100][101]2.3.3 临床数据 Clarity AD试验:主要终点达成: 18个月时CDR-SB评分恶化减缓27%(0.45分 vs 0.67分,p<0.001),这是抗Aβ抗体试验中最强的临床信号[102][103]次要终点: ADAS-Cog14:改善26%(p<0.001) ADCOMS:改善24%(p<0.001) 日常生活能力(ADCS-MCI-ADL):改善37%(p<0.001)[104]Aβ清除: PET显像显示18个月时Aβ斑块负荷降低68.1%,59.1%患者达到淀粉样蛋白阴性[105]生物标志物改变: 血浆p-tau217降低26.9%,提示下游病理减轻[106] 长期扩展研究(AHEAD 3-45):正在进行的研究评估lecanemab在临床前AD(仅有Aβ沉积无症状)患者中的预防作用[107]。安全性特征:ARIA-E: 12.6%(vs 安慰剂1.7%),其中大多数为轻至中度,通常在3个月内消退[108]ARIA-H: 17.3%(微出血14.0%,含铁血黄素沉积8.3%)[109]严重不良事件: 总体发生率与安慰剂相似(14.0% vs 11.3%)[110]APOE ε4相关风险: ε4纯合子ARIA-E发生率达33.5%,但仍低于aducanumab[111]2.3.4 临床应用考量适合人群: 确诊的早期AD(MCI或轻度痴呆阶段) 生物标志物证实的Aβ阳性(通过PET或CSF) MMSE评分≥22[112] 监测要求: 治疗前进行MRI基线扫描,排除已存在的微出血/出血前7个月每3个月进行一次MRI监测ARIA APOE ε4基因型检测推荐但非强制[113] 实际疗效意义:多项分析显示lecanemab的疗效具有临床意义[114][115]: 27%的减缓相当于延迟疾病进展约7.5个月预计可推迟患者需要全时照护的时间约2-3年[116] 成本效益分析显示,尽管年治疗费用$26,500,但考虑到照护成本节省,仍具有卫生经济学价值[117]2.4 Donanemab (Kisunla):最新且可能最有效2.4.1 开发历程 Donanemab由Eli Lilly独立开发,采用了与前两款抗体不同的靶向策略,专注于成熟的斑块形式[118][119]。临床试验时间线:2017-2021: II期试验TRAILBLAZER-ALZ(NCT03367403)显示强劲疗效信号[120]2020-2023: III期试验TRAILBLAZER-ALZ 2(NCT04437511)招募1736名早期AD患者[121]2024年7月2日: FDA授予完全批准,成为第二款获完全批准的抗Aβ抗体[122][123]2.4.2 作用机制 Donanemab的独特性在于其高度特异的靶点选择[124][125]:主要靶点:N3pG-modified Aβ (N端第3位谷氨酸发生焦谷氨酸化修饰的Aβ),这是沉积在脑斑块中的主要Aβ形式,占斑块Aβ的50-90%[126]靶向逻辑: N3pG修饰仅发生在聚集/沉积的Aβ中,可溶性Aβ不具有此修饰,因此donanemab几乎不结合可溶性Aβ或CAA相关的Aβ[127]清除机制: 高亲和力结合成熟斑块,募集小胶质细胞进行快速吞噬清除[128]独特特征: "治疗至斑块清除"策略—一旦PET显示Aβ斑块降至阴性阈值以下,即可停药[129]2.4.3 临床数据 TRAILBLAZER-ALZ 2试验:该试验采用创新的分层设计,根据基线tau病理分为低/中度tau组和高tau组[130]。主要终点(iADRS综合评分):低/中度tau组: 76周时减缓35%(p<0.001),这是迄今抗Aβ抗体试验中最强的疗效信号[131]全体人群: 减缓22%(p=0.004)[132]高tau组: 疗效减弱(仅11%,未达统计显著性),提示tau病理晚期患者获益有限[133] 次要终点:CDR-SB: 低/中度tau组减缓36%,全体减缓29%[134]ADAS-Cog13: 减缓26%[135]Aβ清除: 76周时PET显示Aβ负荷降低84.8%,80.1%患者达到淀粉样蛋白阴性[136]血浆p-tau217: 降低高达43%,提示强劲的下游病理改善[137] 停药策略的可行性:40.9%的donanemab治疗患者在76周内达到Aβ阴性并停药,其中大多数在停药后仍维持临床获益[138]。这一策略可能显著降低长期治疗成本和ARIA风险。安全性特征:ARIA-E: 24.0%(vs 安慰剂1.9%)[139]ARIA-H: 31.4%(微出血19.7%),高于lecanemab,可能与对斑块的强力清除作用有关[140]3例ARIA相关死亡: 引发关注,但因果关系尚不明确(可能与合并使用抗凝药物有关)[141]APOE ε4纯合子: ARIA-E发生率达到40-50%,需谨慎评估风险-获益比[142]2.5 三款抗体的结构差异与结合特性比较2.5.1 结构特征尽管三款抗体均为人源化IgG1,但在结合特异性和亲和力上存在显著差异[143][144]。表3. 三款抗体的结合特性详细比较特性AducanumabLecanemabDonanemab结合表位 Aβ N端(aa 3-7) Aβ中段/C端 N3pG-modified Aβ(N端焦谷氨酸化)对可溶性单体亲和力低极低(Kd>100 nM) 无/极低对原纤维亲和力中等极高(Kd<0.3 nM) 低(因不含N3pG)对成熟斑块亲和力高中等极高对CAA结合高中等低Aβ选择性指数广谱(寡聚体+纤维) 高度选择(原纤维>其他形式1000倍) 极高选择(仅N3pG修饰)体外Aβ清除EC50 0.5-2 nM 0.3 nM 0.1-0.5 nM2.5.2 分子机制解析 Aducanumab的"广谱"问题:Aducanumab结合Aβ的N端3-7位氨基酸序列(EFRH),该表位在所有聚集形式和部分单体中暴露[145]。这导致: 同时结合可溶性寡聚体和不溶性斑块强烈结合血管淀粉样变(CAA),这被认为是高ARIA-E发生率的主要原因[146][147] 可能耗竭部分具有保护作用的可溶性Aβ[148] Lecanemab的"精准打击":Lecanemab通过识别Aβ聚集过程中形成的构象表位,实现高选择性[149][150]: 原纤维的β折叠结构暴露特定的构象表位,lecanemab仅识别此构象对可溶性单体和成熟纤维的亲和力比原纤维低1000-10000倍对CAA的结合显著低于aducanumab,可能解释了其较低的ARIA发生率[151][152] Donanemab的"后修饰特异性":N3pG修饰是Aβ聚集后发生的不可逆化学变化,仅存在于沉积的斑块中[153][154]: Donanemab的抗原识别完全依赖于焦谷氨酸化修饰,几乎不结合未修饰的Aβ CAA中的Aβ较少发生N3pG修饰,因此donanemab对CAA结合力极低[155] 这一特性理论上应降低ARIA风险,但实际临床数据显示ARIA-H发生率反而最高,可能与快速斑块清除导致的局部组织反应有关[156]2.6 结合能力越强,疗效是否越好?深度分析这是AD药物开发中的一个关键悖论:更强的Aβ结合力不一定带来更好的临床疗效,反而可能增加安全性风险[157][158]。2.6.1 Aβ清除率与认知疗效的关系表4. 三款抗体的Aβ清除与认知改善对比指标AducanumabLecanemabDonanemabPET Aβ清除率(%) 59-71%(78周) 68.1%(18个月) 84.8%(76周)认知减缓(CDR-SB) 22-23%(18个月,EMERGE) 27%(18个月) 29-36%(76周,分层)ARIA-E发生率(%) 35.2% 12.6% 24.0%ARIA-H发生率(%) 19.1% 17.3% 31.4%治疗中断率(%) 高(约25-30%) 低(约6.9%) 中等(约14%) 关键发现:Aβ清除与疗效非线性关系: Donanemab的Aβ清除率最高(84.8%),认知疗效也最强;但aducanumab清除率达59-71%时,疗效仅22%且试验结果不一致[159][160]。"最佳靶点"假说: Lecanemab的数据支持"靶向中间聚集体(原纤维)比终末聚集体(成熟斑块)更有效"的理论,因为原纤维是当前正在行使毒性的形式,而成熟斑块可能已相对惰性[161][162]。时机窗口至关重要: TRAILBLAZER-ALZ 2显示,在低/中度tau患者(疾病更早期)中疗效显著更强(35% vs 11%),提示Aβ清除的获益在tau病理尚未广泛扩散前最大[163][164]。2.6.2 ARIA风险与结合特性的关系多项研究揭示了ARIA发生机制与抗体结合特性的复杂关系[165][166]: ARIA-E(水肿/渗出):主要机制: 抗体结合CAA引发血管炎症反应,导致血-脑屏障(BBB)破坏[167]与CAA结合力的相关性: Aducanumab > Donanemab > Lecanemab(与ARIA-E发生率趋势一致)[168][169]2025年体外研究: 使用人脑组织切片的结合实验显示,aducanumab对CAA的结合信号强度是lecanemab的3-5倍[170] ARIA-H(微出血):主要机制: 快速斑块清除导致血管周围组织结构改变,或直接损伤血管壁[171]与清除速度的相关性: Donanemab > Lecanemab > Aducanumab(donanemab最快清除斑块,ARIA-H也最高)[172]悖论现象: Donanemab对CAA结合力最低,但ARIA-H最高,提示其他机制参与(如快速吞噬反应引发的局部炎症)[173]2.6.3 "Goldilocks原则"—恰到好处的结合力系统性比较研究提出了**"适度结合假说"(Moderate Binding Hypothesis)**[174][175]:过强结合(如aducanumab对CAA): 导致过度免疫激活,BBB破坏,ARIA-E高发过弱结合: 无法有效清除Aβ,疗效不足(如早期失败的crenezumab)[176]适度且选择性结合(如lecanemab): 有效清除致病性Aβ形式,同时最小化对血管和非致病性Aβ的影响 2024年计算建模研究[177]: 使用分子动力学模拟和平衡结合实验,研究者发现: Lecanemab对原纤维的结合亲和力(Kd≈0.3 nM)与其对斑块Aβ的清除能力和ARIA风险之间达到最优平衡 Aducanumab对所有形式Aβ的"无差别"高亲和力(Kd≈0.5-2 nM)导致靶向特异性不足 Donanemab对N3pG-Aβ的极高特异性(Kd<0.1 nM)虽然最小化了脱靶效应,但快速清除动力学可能触发过度的炎症反应2.6.4 结论:疗效取决于"靶向精准度",而非单纯"结合强度" 综合证据支持以下结论[178][179][180]:精准性>强度: Lecanemab的成功表明,高度选择性靶向毒性Aβ形式(原纤维)比广谱高亲和力结合更有效且更安全疾病阶段匹配: Donanemab在低tau患者中的卓越疗效(35%)表明,斑块清除的获益窗口在疾病早期;晚期患者tau病理占主导,单纯清除Aβ收益有限风险-获益平衡: Lecanemab的中等ARIA发生率(ARIA-E 12.6%)和强劲疗效(27%)使其成为当前最优选择;Donanemab虽疗效更强但ARIA-H风险也更高,需个体化权衡未来方向: 下一代抗体应优化靶向特异性(如lecanemab)同时提高清除效率(如donanemab的停药策略),并开发ARIA预测和预防策略3. 已失败的AD药物:教训与启示 AD药物开发是失败率最高的领域之一,2002-2022年间成功率仅3.6%[181][182]。理解失败原因对未来药物开发至关重要。3.1 失败药物汇总表5. 主要失败的AD候选药物(2012-2024)药物名称作用机制靶点制造商失败阶段失败时间失败原因抗Aβ单克隆抗体 Bapineuzumab 被动免疫 Aβ N端(1-5) Pfizer/JNJ Phase 3 2012年8月无效+高ARIA(APOE ε4携带者)[183][184] Solanezumab 被动免疫可溶性Aβ单体(16-26) Eli Lilly Phase 3 2016年11月无认知改善(EXPEDITION-3)[185][186] Gantenerumab 被动免疫 Aβ N端+C端(构象表位) Roche Phase 3 2022年11月 Aβ清除显著但无认知获益(GRADUATE 1&2)[187][188] Crenezumab 被动免疫 Aβ寡聚体(IgG4,低效应功能) Roche/Genentech Phase 3 2019年1月无效(CREAD 1&2)[189][190] Ponezumab 被动免疫 Aβ C端(33-40) Pfizer Phase 2 2012 无效 [191]BACE抑制剂(口服小分子) Verubecestat (MK-8931) BACE1抑制 β分泌酶 Merck Phase 3 2017年2月无效+认知恶化趋势(EPOCH)[192][193] Lanabecestat (AZD3293) BACE1抑制 β分泌酶 Eli Lilly/AstraZeneca Phase 3 2018年6月无效+认知恶化(AMARANTH/DAYBREAK)[194][195] Atabecestat (JNJ-54861911) BACE1抑制 β分泌酶 Janssen/JNJ Phase 2/3 2018年5月肝酶升高安全性问题[196][197] Elenbecestat (E2609) BACE1抑制 β分泌酶 Eisai/Biogen Phase 3 2019年9月无效+体重减轻/睡眠障碍(MISSION AD1&2)[198][199] Umibecestat (CNP520) BACE1抑制 β分泌酶 Novartis/Amgen Phase 2/3 2019年7月认知恶化(预防试验)[200][201] LY3202626 BACE1抑制 β分泌酶 Eli Lilly Phase 2 2018年10月无效可能性高,提前终止[202]γ分泌酶调节剂 Semagacestat (LY450139) γ分泌酶抑制 γ分泌酶 Eli Lilly Phase 3 2010年8月认知恶化+皮肤癌风险↑[203][204] Avagacestat (BMS-708163) γ分泌酶抑制 γ分泌酶 Bristol-Myers Squibb Phase 2 2012 皮肤癌+无效[205]抗Tau抗体 Gosuranemab (BIIB092) 被动免疫细胞外tau(N端) Biogen Phase 2 2021年12月无临床获益[206][207] Tilavonemab (ABBV-8E12) 被动免疫细胞外tau AbbVie Phase 2 2019年7月无效[208][209] Semorinemab (RO7105705) 被动免疫细胞外tau(N端) Roche/Genentech Phase 2 2021年8月无效[210][211] Zagotenemab (LY3303560) 被动免疫细胞外tau(微管结合区) Eli Lilly Phase 2 2020 无效[212]其他机制 Azeliragon (TTP488) RAGE拮抗剂晚期糖基化终产物受体 vTv Therapeutics Phase 3 2018年无效[213] Masitinib 酪氨酸激酶抑制 KIT/CSF1R(神经炎症) AB Science Phase 3 2024年(EMA拒绝) 疗效证据不足,设计缺陷[214][215]3.2 失败模式分析3.2.1 抗Aβ抗体失败:从Bapineuzumab到Gantenerumab Bapineuzumab(2012):机制: 靶向Aβ N端1-5位氨基酸,与天然抗体3D6相似[216]失败原因: 两项III期试验(研究301, 302)未达主要终点[217] APOE ε4携带者ARIA-E发生率高达15%(非携带者<2%)[218] 可能过于强烈结合CAA,导致血管并发症限制了剂量提升[219]教训: APOE ε4基因型需纳入试验分层;CAA结合需最小化 Solanezumab(2016):机制: 靶向可溶性Aβ单体中段(16-26位),理论上阻止聚集[220]失败原因: EXPEDITION-3试验(2129名轻度AD患者)主要终点阴性[221] 尽管降低了CSF可溶性Aβ,但不清除脑内斑块(PET无变化)[222] 事后分析提示可能需要更早期干预(临床前阶段)[223]教训: 单纯结合可溶性Aβ单体不足以产生临床获益;需要实际清除聚集体 Gantenerumab(2022):机制: 完全人源IgG1,结合Aβ N端和C端的构象表位,高Fc介导吞噬能力[224]失败原因: GRADUATE 1&2试验显示Aβ斑块清除显著(高剂量组-54.8%),但CDR-SB无统计学改善[225][226] 可能剂量仍不足,或患者选择过晚(包含较多中度AD患者)[227] ARIA发生率高(ARIA-E 19.6%, ARIA-H 28.7%),限制了剂量提升[228]教训: Aβ清除是必要但非充分条件;疾病阶段选择至关重要 Crenezumab(2019):机制: IgG4抗体,低Fc效应功能,靶向Aβ寡聚体[229]失败原因: IgG4设计初衷是降低ARIA风险,但同时降低了清除效率[230] CREAD试验显示Aβ清除非常有限,无临床获益[231]教训: 过度降低免疫效应功能会牺牲疗效;IgG1可能是必须的3.2.2 BACE抑制剂的"集体阵亡" BACE(β-site APP-cleaving enzyme)抑制剂理论上可从源头阻断Aβ生成,但至少6款候选药物在2017-2019年集体失败,引发对该策略的根本性质疑[232][233]。共同失败特征:认知恶化: 多项试验观察到治疗组认知评分恶化快于安慰剂组[234][235]生理功能障碍: 体重减轻、睡眠障碍、毛发/皮肤颜色改变等[236]生物标志物矛盾: CSF Aβ42降低(符合预期),但tau/p-tau未改善,甚至升高[237] 失败机制解析:BACE1的生理功能广泛: BACE1不仅切割APP,还处理其他重要底物(如神经调节素、Na通道β亚单位、SEZ6),过度抑制导致多种生理功能障碍[238][239]时机窗口已过: AD患者脑内Aβ沉积已持续10-20年,此时阻断新生成的Aβ可能为时已晚[240]补偿性Aβ上调: 长期抑制BACE1可能触发APP表达上调等补偿机制[241] Verubecestat的警示案例: Merck的verubecestat是首个失败的BACE抑制剂,2017年EPOCH试验(1958名轻至中度AD患者)显示高剂量组认知恶化反而更快[242][243] 这一结果震惊了整个领域,并引发了对"Aβ假说"本身的质疑[244] 教训: BACE抑制可能不适合有症状的AD患者,但在临床前阶段(Aβ刚开始累积时)可能仍有潜力[245] DIAN-TU正在遗传性AD高危人群中测试BACE抑制剂的预防作用[246]3.2.3 抗Tau抗体:为何全军覆没? 至今已有至少4款抗tau抗体在II期试验失败,无一进入III期[247][248]。共同失败特征: CSF tau降低(证实靶点接合),但无临床获益[249] PET tau未显著改变[250] 失败原因分析:靶向细胞外tau的局限: 这些抗体均靶向细胞外tau,但AD中tau病理主要在细胞内(神经纤维缠结),细胞外tau可能只是"旁观者"而非主要致病因子[251][252]疾病阶段过晚: 当患者已有临床症状时,神经元大量丧失,清除tau可能无法逆转已发生的损伤[253]tau传播机制复杂: Tau通过突触连接传播,单纯中和细胞外tau可能无法阻断传播[254] 教训: 未来tau疗法可能需要进入细胞内(如ASO反义寡核苷酸降低tau表达)[255] 或在疾病更早期(MCI阶段)干预[256]3.3 系统性教训总结 AD药物失败率如此之高,根本原因包括[257][258]:疾病异质性: AD不是单一疾病,而是多种病理过程的综合征(Aβ、tau、神经炎症、血管损伤、代谢异常等)[259]时机窗口: 大多数试验纳入症状明显的患者,此时神经元损伤已不可逆;需要更早期干预[260]生物标志物盲目性: 早期试验未强制要求Aβ/tau阳性证实,导致纳入非AD患者稀释疗效信号[261]评估终点不敏感: 传统认知量表(ADAS-Cog, MMSE)在早期AD患者中变化缓慢,难以捕捉轻微改善[262]单一靶点局限: AD是多因素疾病,单一靶点干预可能不足[263] 这些教训推动了当前试验设计的改进:生物标志物证实、早期干预、复合终点、精准分层[264][265]。4. 在研靶向药物管线(2025) 尽管经历了无数失败,AD药物管线依然活跃。2025年报告显示,有138个新药在182项临床试验中,较2024年增长9%[266][267]。4.1 在研靶向药物列表表6. 主要在研靶向药物(2025年更新)药物名称靶点作用机制制造商研究阶段预期完成时间特色/创新点临床试验编号抗Aβ靶向 Remternetug (LY3372993) Aβ原纤维单抗,类似lecanemab Eli Lilly Phase 3 2026年皮下注射剂型,改善便利性[268] NCT05463731 ALZ-801 (valiltramiprosate) Aβ寡聚体小分子,阻止聚集 Alzheon Phase 3 2025年口服,靶向可溶性寡聚体[269] NCT04770220抗Tau靶向 E2814 细胞外tau(MTBR) 单抗,Fc沉默 Eisai Phase 2 2026年靶向微管结合区tau[270][271] NCT04971733 Bepranemab (UCB0107) 细胞外tau(mid-region) 单抗 UCB Phase 2b 2027年首个显示PET tau降低的抗体[272][273] NCT05269394 Lu AF87908 细胞外tau(phospho-tau) 单抗,靶向p-tau Lundbeck Phase 2 2026年特异性靶向磷酸化tau[274] NCT04149860Tau ASO(反义寡核苷酸) BIIB080 (IONIS-MAPTRx) MAPT mRNA ASO,降低tau表达 Biogen/Ionis Phase 2 2025年鞘内给药,直接降低tau蛋白生成[275][276] NCT05399888 ACI-7104 Tau蛋白主动免疫(疫苗) AC Immune Phase 1b/2a 2026年刺激内源抗tau抗体产生[277] NCT05798078双靶点/多靶点 Xanamem (UE2343) 11β-HSD1抑制小分子,降低脑内皮质醇 Actinogen Medical Phase 2 2025年代谢-神经保护双重作用[278] NCT04750954 Troriluzole 谷氨酸调节小分子,PSD-95抑制 Biohaven Phase 3 (失败) 2021年突触保护[279] -4.1.1 Trontinemab:罗氏的优化尝试 Trontinemab (RO7126209)是罗氏在gantenerumab失败后开发的新一代抗Aβ抗体,通过优化选择性(高亲和力结合原纤维,低结合单体)和减弱Fc功能降低ARIA风险[503][504]。关键数据: Phase 1显示ARIA-E发生率12%(vs lecanemab 13%),ARIA-H8%(vs lecanemab 17%)[505][506]SKYLINE Phase 2/3 (NCT06049329):1400名早期AD患者,4500mg Q4W,主要终点CDR-SB(18个月),预计2027年中期完成[507][508] **差异化定位:**月度给药+更低出血风险,但需证明疗效不劣于lecanemab才具竞争力[509][510]。4.2 重点在研药物详述4.2.1 E2814:新一代抗Tau抗体开发背景: Eisai开发的E2814是目前最先进的抗tau抗体,与前代失败药物的关键区别在于靶向tau蛋白的微管结合区(MTBR)[280][281]。作用机制: 特异性结合细胞外tau的MTBR区域,该区域对tau聚集和毒性至关重要[282] Fc区域沉默设计,降低免疫激活风险[283] 阻断tau在神经元间的扩散传播[284] 临床进展: Phase 2研究(NCT04971733)在早期AD患者中进行,主要终点包括认知功能和PET tau变化[285] 初步数据显示良好的安全性和靶点接合证据(CSF tau降低)[286] Phase 2/3 FRONTIER-AD研究(NCT05269394)正在进行中,预计2027年公布结果[287] 创新点: 如果成功,E2814将证明靶向MTBR比N端更有效,为tau疗法开辟新路径。4.2.2 Bepranemab:首个显示PET tau降低的抗体开发背景: UCB公司的bepranemab是首个在临床试验中显示出PET tau成像降低的抗tau抗体,在2024年CTAD会议上公布的数据引发关注[288][289]。作用机制: 靶向细胞外tau的中段区域(与前代药物不同)[290] IgG4骨架,降低Fc效应功能[291] 临床数据(Phase 2初步结果):PET tau降低: 52周治疗后,颞叶PET tau信号降低15-20%(剂量依赖性),这是抗tau抗体首次显示的客观影像学证据[292][293]认知信号: CDR-SB显示减缓趋势(约18%),但未达统计显著性(样本量较小,n=157)[294]安全性: 良好耐受,无ARIA或严重不良事件增加[295] 意义: Bepranemab的PET tau降低数据打破了"抗tau抗体无效"的魔咒,为该领域注入新希望。Phase 2b扩展研究(SAKURA, NCT05269394)正在招募更大样本量以验证疗效[296]。4.2.3 BIIB080:开创性的Tau ASO疗法技术背景: BIIB080(原名IONIS-MAPTRx)是首个进入临床试验的tau反义寡核苷酸(antisense oligonucleotide, ASO),代表了与抗体完全不同的tau靶向策略[297][298]。作用机制: ASO通过互补配对结合MAPT(tau基因)的mRNA,募集RNase H酶降解mRNA[299] 直接从源头降低tau蛋白表达,包括细胞内和细胞外tau[300] 鞘内注射给药,绕过血脑屏障,直接进入CSF并被神经元摄取[301] 临床进展: Phase 1/2研究(NCT03186989): 46名轻度AD患者接受鞘内注射,结果于2021年公布[302][303]:CSF tau降低: 高剂量组(100 mg)在13周时CSF总tau降低50%以上,效果持续至25周[304]安全性: 整体良好耐受,主要不良反应为鞘内注射相关(头痛、腰痛),无神经系统严重不良事件[305]认知信号: 探索性分析显示认知稳定趋势,但研究未设计为评估疗效[306] Phase 2研究(CELIA, NCT05399888): 正在早期AD患者中进行,评估不同剂量方案对认知功能的影响[307]: 主要终点:CDR-SB变化(52周)[308] 次要终点:CSF tau、PET tau、脑萎缩速度[309] 预计完成时间:2025年底[310] 创新意义:首个"源头治疗": 降低tau蛋白生成而非清除已形成的病理,理论上更根本[311]细胞内作用: 克服了抗体无法进入细胞内的局限[312]技术平台价值: 如果成功,将为其他神经退行性疾病(如FTD、PSP)的ASO疗法铺路[313] 挑战: 鞘内给药的侵入性和不便性(每3-4个月一次腰椎穿刺)[314] 长期安全性未知(tau在神经系统中具有生理功能)[315] 是否需要终身治疗尚不明确[316]4.2.4 Remternetug:皮下注射的便利性革命开发背景: Eli Lilly开发的remternetug (LY3372993)与lecanemab类似,同样靶向Aβ原纤维,但关键创新在于给药方式[317][318]。作用机制: 单克隆抗体,高选择性结合Aβ可溶性原纤维[319] 作用机制与lecanemab基本相同,但经过优化以适合皮下给药[320] 给药创新:皮下注射剂型: 患者或照护者可在家自行注射,无需每2周到医院输液[321]自动注射笔: 类似糖尿病胰岛素笔,极大提高依从性[322]给药频率: 每周一次或每两周一次(剂量优化中)[323] 临床进展:Phase 2研究(NCT04629937): 2021-2023年在早期AD患者中完成,初步数据显示[324]: 生物标志物接合:血浆Aβ42/40比值改善,提示脑内Aβ清除[325] 安全性:ARIA发生率与lecanemab相似(ARIA-E约12-15%),但注射部位反应发生率约30%[326]Phase 3研究(TRAILRUNNER-ALZ 1&2, NCT05463731/NCT05508789): 2022年启动,预计2026年完成[327][328]: 目标招募1650名早期AD患者[329] 主要终点:CDR-SB(18个月)[330] 关键设计:与lecanemab头对头比较的优效性试验[331] 市场意义: 如果疗效与lecanemab相当,皮下剂型将成为巨大竞争优势[332] 降低医疗系统负担(无需输液中心资源)[333] 患者生活质量显著提升(避免每两周医院往返)[334]4.2.5 ALZ-801:重启的口服小分子希望历史背景: ALZ-801(valiltramiprosate)是tramiprosate的前药,后者曾在2007年Phase 3失败,但ALZ-801通过改进药代动力学获得新生[335][336]。作用机制: 小分子,与Aβ单体结合,阻止其聚集为寡聚体和原纤维[337][338] 不清除已形成的斑块,而是"预防"新聚集形成[339] 口服给药,跨越血脑屏障[340] 关键改进(vs tramiprosate): 前药设计提高生物利用度,降低胃肠道副作用[341] 优化剂量方案(265 mg BID)[342] 临床进展:Phase 2研究(COGNITE): 在APOE ε4/ε4纯合子早期AD患者中进行,显示初步疗效信号[343]: 该人群疾病进展快,理论上更容易观察到疗效[344] 海马萎缩速度减缓42%(p=0.035)[345] 认知功能(ADAS-Cog14)改善趋势,但未达统计显著[346]Phase 3研究(APOLLOE4, NCT04770220): 专注于APOE ε4/ε4纯合子人群[347]: 目标招募350名早期AD患者[348] 主要终点:ADAS-Cog14(78周)[349] 预计完成:2025年中[350]独特设计: 首个专门针对APOE ε4纯合子的Phase 3试验,这一人群占AD患者的10-15%,进展速度是平均水平的2-3倍[351] 优势: 口服便利性,无ARIA风险[352] 可能作为抗体疗法的辅助或替代选择(特别是抗体不耐受或禁忌患者)[353] 成本潜在更低[354] 挑战: 小分子阻止聚集的效果是否足以产生临床意义的认知改善仍待验证[355] 前代tramiprosate的失败阴影[356]5. 在研非靶向治疗机制:多样化的创新策略随着Aβ/tau靶向疗法的局限性逐渐显现,研究者转向AD的其他病理机制,开辟了多条创新治疗路径[357][358]。5.1 在研非靶向药物列表表7. 主要在研非靶向治疗药物(2025年更新)治疗机制药物名称作用机制/靶点制造商研究阶段主要疗效/证据预期完成临床试验编号神经炎症调节 Masitinib 酪氨酸激酶抑制(c-Kit/CSF1R),抑制小胶质细胞过度激活 AB Science Phase 3(争议) 轻至中度AD:ADAS-Cog改善1.5分(18个月);EMA拒批[359][360] 2024(已拒) NCT01872598 AL002 (latozinemab) 抗TREM2单抗,增强小胶质细胞功能 Alector/GSK Phase 2 Phase 1显示TREM2靶点接合;Phase 2进行中[361][362] 2026年 NCT04592874 AL003 (zamidemab) 抗CD33单抗,调节小胶质细胞 Alector Phase 2 降低可溶性CD33,减少神经炎症[363] 2025年 NCT05715749 Sargramostim (GM-CSF) 粒细胞-巨噬细胞集落刺激因子,增强小胶质细胞Aβ清除 Partner Therapeutics Phase 2 初步数据显示MMSE改善趋势[364] 2024年 NCT04902703 代谢/线粒体功能 GV-971 (sodium oligomannate) 海洋寡糖,调节肠道菌群-脑轴,降低神经炎症 Shanghai Green Valley 中国已批准中国Phase 3:ADAS-Cog12改善2.54分(36周);美国Phase 3进行中[365][366] 2025年(美国) NCT04520412 CMS121 线粒体调节剂 Cognition Therapeutics Phase 2 改善线粒体功能,减少氧化应激[367] 2025年 NCT04845282 KarXT (xanomeline-trospium) M1/M4毒蕈碱受体激动剂 Karuna/BMS Phase 2 改善认知和精神症状,特别是激越[368][369] 2025年 NCT05797519 血管/脑血流 Neflamapimod (VX-745) p38α MAPK抑制剂,改善突触功能和脑血流 EIP Pharma Phase 2 早期AD:改善情景记忆;Phase 2b未达主要终点[370][371] 2023(失败) NCT03402659 Azeliragon (TTP488) RAGE拮抗剂,改善脑血流和血脑屏障 vTv Therapeutics Phase 3(失败) 无效;T2DM合并AD亚组有趋势[372] 2018(终止) NCT02080364 突触保护/神经营养 Fosgonimeton (ATH-1017) HGF/c-Met激活剂,促进突触再生 Athira Pharma Phase 2 Phase 2显示生物标志物改善,但Phase 2/3(ACT-AD)未达终点[373][374] 2023(失败) NCT04488419 Mevidalen (LY3372689) O-GlcNAcase抑制剂,增强突触功能 Eli Lilly Phase 2 改善tau磷酸化和突触蛋白[375] 2025年 NCT05063539 胆碱能增强(新机制) T-817MA 神经保护剂,增强胆碱能+抗氧化 Toyama/Fujifilm Phase 3(日本) 日本Phase 2显示ADAS-Cog改善[376] 2024年 - 激素调节 Xanamem (UE2343) 11β-HSD1抑制剂,降低脑内皮质醇 Actinogen Phase 2 改善认知和脑代谢(FDG-PET)[377][378] 2025年 NCT04750954 表观遗传调节 Sodium phenylbutyrate + Tauroursodeoxycholic acid (PB+TUDCA) HDAC抑制+ER应激缓解 Amylyx (已停产) Phase 3(失败) ALS适应症失败;AD试验未进行[379] - - 神经再生/干细胞 Lomecel-B 同种异体间充质干细胞 Longeveron Phase 2b 改善炎症标志物,认知信号待证实[380][381] 2025年 NCT04228666 肠道菌群调节 AXON-501 益生菌混合物,调节肠-脑轴 Axon Neuroscience Phase 2 初步数据显示炎症标志物改善[382] 2026年 NCT05686629 关键数据: Phase 1显示ARIA-E发生率12%(vs lecanemab 13%),ARIA-H8%(vs lecanemab 17%)[505][506]SKYLINE Phase 2/3 (NCT06049329):1400名早期AD患者,4500mg Q4W,主要终点CDR-SB(18个月),预计2027年中期完成[507][508] 差异化定位:月度给药+更低出血风险,但需证明疗效不劣于lecanemab才具竞争力[509][510]。5.2 重点非靶向机制深度解析5.2.1 神经炎症靶向:从破坏到修复理论基础:神经炎症是AD的核心病理特征,小胶质细胞和星形胶质细胞的慢性激活导致神经元损伤[383][384]。然而,炎症在AD中扮演双刃剑角色:早期可能是保护性的(清除Aβ),但慢性激活转为破坏性(释放促炎因子、吞噬突触)[385][386]。因此,治疗策略需要"精准调节"而非简单"抑制"。 AL002 (latozinemab) - TREM2激动:TREM2(Triggering Receptor Expressed on Myeloid cells 2): 小胶质细胞表面受体,其功能缺失突变显著增加AD风险(OR=2-4)[387][388]作用机制: AL002激动TREM2,增强小胶质细胞的"良性"功能(Aβ吞噬、碎片清除),同时抑制过度炎症反应[389][390]Phase 1数据: 安全性良好,CSF可溶性TREM2增加(证实靶点接合)[391]Phase 2进展(INVOKE-2, NCT04592874): 在早期AD患者中评估认知和生物标志物变化,预计2026年公布[392] 挑战: TREM2激动是否真正转化为临床获益尚待验证;小胶质细胞激活的时机和程度难以精准控制[393]。 Masitinib争议: 2024年,EMA拒绝批准masitinib用于轻至中度AD,理由是Phase 3试验(AB09004)存在设计缺陷、疗效证据不充分[394][395] 然而,一项独立meta分析显示,masitinib在快速进展的AD亚组中可能有效(ADAS-Cog改善约1.5-2分)[396] 教训:神经炎症调节剂需要更精准的患者选择(如基于神经炎症PET成像分层)[397]5.2.2 肠道菌群-脑轴:GV-971的中国奇迹? GV-971 (Sodium Oligomannate):发现: 由中国科学院、上海药物所和上海绿谷制药联合开发,从海洋褐藻中提取的寡糖衍生物[398]作用机制(多靶点): [399][400]肠道菌群重塑: 抑制条件致病菌(如Bacteroides fragilis),增加有益菌,降低肠道产生的神经毒性代谢物(如苯丙氨酸和异亮氨酸)[401]外周免疫调节: 减少促炎性Th1细胞向脑内浸润[402]中枢神经炎症抑制: 降低小胶质细胞和星形胶质细胞激活[403]直接神经保护: 可能具有抗Aβ聚集作用[404] 临床数据: Phase 3试验(中国,NCT02293915): 818名轻至中度AD患者,36周[405][406]:主要终点: ADAS-Cog12评分改善2.54分 vs 安慰剂(p<0.0001)[407]安全性: 良好耐受,主要不良反应为轻度腹泻(约10%)[408]争议: 试验设计和数据透明度受到国际质疑,特别是效应量在后期突然放大[409][410] 2019年11月: 中国国家药品监督管理局(NMPA)附条件批准,成为17年来中国首个原创AD新药[411] Phase 3试验(美国,OCEAN, NCT04520412): 2020年启动,计划招募1200名患者,预计2025年完成[412][413] 意义与争议:创新点: 首个基于"肠道菌群-免疫-脑轴"理论的AD药物,开辟新治疗范式[414]争议点: 作用机制过于复杂,难以确定主要有效成分[415] 中国Phase 3数据的可重复性待美国试验验证[416] 2.54分ADAS-Cog改善的临床意义与胆碱酯酶抑制剂相当,是否具有显著优势?[417] 最新进展(2024-2025): 发表在Cell Research的机制研究揭示了GV-971通过重塑肠道菌群代谢组减少外周免疫细胞脑浸润的详细分子通路[418] 美国试验招募进展缓慢,FDA要求更严格的数据监测[419]5.2.3 代谢与线粒体靶向:能量危机的解决方案理论基础:AD脑内存在显著的代谢功能障碍,包括葡萄糖利用降低(FDG-PET显示)、线粒体功能受损、氧化应激增加[420][421]。这些改变可能早于Aβ沉积和tau病理,提示代谢干预可能是早期预防的关键[422]。 Xanamem (UE2343) - 皮质醇调节:靶点: 11β-HSD1(11β-hydroxysteroid dehydrogenase type 1),该酶在脑内将无活性的可的松转化为活性皮质醇[423]AD中的作用: 慢性应激和衰老导致脑内皮质醇水平升高,损伤海马神经元、诱导胰岛素抵抗、加重Aβ和tau病理[424][425]作用机制: Xanamem选择性抑制11β-HSD1,降低脑内皮质醇,改善糖代谢和神经元健康[426] 临床数据:Phase 2研究(XanaMIA, NCT03450005): 174名轻度AD患者,12周[427]:认知改善: NeuroCart认知测试组合显示注意力和执行功能改善[428]脑代谢: FDG-PET显示海马和颞叶葡萄糖利用增加约8-10%[429]生物标志物: 血浆Aβ42/40比值改善趋势[430]Phase 2b研究(XanADu, NCT04750954): 正在进行,评估26周治疗对认知和功能的影响[431] 意义: Xanamem代表了"代谢修复"策略,可能与Aβ/tau靶向疗法协同使用[432]。 CMS121 - 线粒体靶向:机制: 通过稳定线粒体膜电位、增强ATP生成、减少活性氧(ROS)产生来保护神经元[433]Phase 2初步数据: 显示脑代谢改善和氧化应激标志物降低,但认知终点数据尚未公布[434]5.2.4 突触保护与再生:修复失去的连接理论基础:突触丧失是AD认知衰退最直接的神经解剖学相关因素,比神经元数量减少或Aβ斑块负荷更能预测认知功能[435][436]。突触数量在MCI阶段即已减少20-30%,提示突触保护/再生可能是逆转认知衰退的关键[437]。 Fosgonimeton (ATH-1017)的失败教训:机制: 小分子HGF/c-Met通路激活剂,肝细胞生长因子(HGF)信号激活可促进神经元存活、突触形成和髓鞘修复[438][439]Phase 2结果: 显示CSF神经营养因子增加,突触蛋白(如neurogranin)改善[440]Phase 2/3失败(ACT-AD, 2023): 未达主要认知终点,Athira Pharma股价暴跌80%[441][442]失败原因分析: 生物标志物改善未转化为临床获益(再次证明替代终点的局限)[443] 突触再生可能需要更长时间才能影响认知[444] 或HGF通路在AD晚期已失去反应性[445] Mevidalen (LY3372689) - O-GlcNAcase抑制:创新机制: O-GlcNAc糖基化是一种关键的蛋白质翻译后修饰,调节tau磷酸化、突触蛋白功能和神经元能量代谢[446][447]AD中的作用: O-GlcNAc水平降低导致tau过度磷酸化和突触功能障碍;抑制O-GlcNAcase可恢复正常O-GlcNAc水平[448]Phase 1数据: 安全性良好,CSF生物标志物显示O-GlcNAc水平升高[449]Phase 2进展: 正在评估认知和突触标志物变化,预计2025年公布[450] 意义: 如果成功,将证明"翻译后修饰调节"这一全新治疗范式的可行性[451]。5.2.5 毒蕈碱受体激动:精神症状的新希望 KarXT (Xanomeline-Trospium):组成: Xanomeline(M1/M4毒蕈碱受体激动剂) + Trospium(外周抗胆碱药,减少外周副作用)[452]作用机制:M1受体激活: 增强认知功能,促进非淀粉样APP切割,降低Aβ生成[453]M4受体激活: 调节多巴胺释放,改善精神症状(激越、妄想、幻觉)[454] 临床进展:Phase 2研究(COGNITION, NCT05797519): 在AD相关激越患者中进行[455]: 主要终点:Cohen-Mansfield激越量表(CMAI)评分改善[456] 初步数据(2024年)显示激越症状显著减轻(效应量d=0.6-0.8)[457]意义: 可能成为首个专门针对AD行为精神症状(BPSD)的获批药物[458] 与抗Aβ抗体联合使用,实现"认知+行为"双重改善[459] Karuna被BMS以140亿美元收购,显示业界对该机制的信心[460]5.3 联合疗法:未来的必然趋势理论基础:AD是多因素疾病,单一靶点干预的天花板效应已显现。类似肿瘤学和HIV治疗,联合疗法可能是实现疾病修饰的唯一路径[461][462]。当前探索的联合策略: 表8. 在研或计划中的联合疗法方案联合方案理论依据临床试验状态预期协同效应 Lecanemab + 抗Tau抗体(如E2814) Aβ驱动tau扩散,双靶点阻断计划中(Eisai) 延缓疾病进展>40%[463] Lecanemab + 神经炎症调节剂 Aβ清除+炎症损伤控制探索中降低ARIA,提高疗效[464] 抗Aβ抗体 + 胆碱酯酶抑制剂疾病修饰+症状控制临床实践中广泛使用疾病进程减缓+认知改善[465] GV-971 + Lecanemab 外周炎症控制+中枢Aβ清除假设性多层次病理阻断[466] 挑战:复杂性: 试验设计难度指数级增加,样本量需求巨大[467]安全性风险: 不良反应叠加或新的相互作用[468]成本: 多药联用的经济负担(lecanemab已$26,500/年)[469]6. 总结与未来展望6.1 当前治疗格局总结已批准疗法(2025):症状性治疗(传统): 3款胆碱酯酶抑制剂 + 1款NMDA拮抗剂,使用20-30年,疗效有限但安全[470]疾病修饰疗法(新): 2款抗Aβ单抗(lecanemab, donanemab),首次证明能减缓认知衰退27-36%,但ARIA风险和高成本限制应用[471][472] 疗效对比: Lecanemab:当前金标准,安全性最佳,27%减缓(CDR-SB,18个月)[473] Donanemab:可能疗效最强(低tau组36%),但ARIA-H风险最高,停药策略创新[474]6.2 未来5年的关键问题抗Aβ抗体的长期疗效: 18个月疗效能否持续至3-5年?[475] 停药后疾病是否反弹?[476] Open-label扩展研究正在回答这些问题[477] 更早期干预: AHEAD 3-45试验(lecanemab预防性使用)将揭示临床前期干预的可行性[478] 如果成功,可能推动无症状Aβ阳性人群的预防性治疗[479] Tau疗法突破: E2814, bepranemab, BIIB080能否成为首个有效的tau疗法?[480] 如果成功,Aβ+tau双靶点联合治疗将成为现实[481] 非侵入性给药: Remternetug(皮下)能否挑战lecanemab?[482] 口服抗Aβ小分子(如ALZ-801)能否证明可行?[483] 精准医疗: 基于APOE基因型、tau PET分期、神经炎症水平的个体化治疗方案[484][485] AI驱动的治疗反应预测模型[486] 非Aβ/tau机制验证: 神经炎症(AL002)、肠道菌群(GV-971)、代谢(xanamem)能否证明独立疗效?[487] 这些机制是否需要与Aβ清除联合才能发挥作用?[488]6.3 对患者和临床医生的启示当前建议(2025):早期诊断至关重要: 抗Aβ抗体仅对早期AD有效,疾病进展至中度后获益有限[489]生物标志物确认必须: 通过Aβ PET或CSF确认Aβ阳性后才应使用抗体疗法[490]ARIA监测不可忽视: 前7个月每3个月MRI监测,APOE ε4纯合子需谨慎评估风险-获益比[491]联合传统疗法: 抗体疗法不应替代胆碱酯酶抑制剂,联合使用可能带来额外获益[492]临床试验参与: 鼓励符合条件的患者参与临床试验,这是获得前沿疗法的重要途径[493]6.4 结语从1993年tacrine的首次批准到2024年donanemab的完全批准,AD药物治疗走过了艰难的30年。尽管经历了无数失败和挫折,lecanemab和donanemab的成功最终证明了Aβ假说的有效性,并为疾病修饰疗法开辟了道路[494][495]。然而,27-36%的疾病减缓仅是开始,而非终点。未来的治疗将可能是:更早期: 在临床前或MCI阶段开始干预[496]更精准: 基于基因组、生物标志物、影像学的个体化方案[497]更全面: Aβ + tau + 炎症 + 代谢的多靶点联合[498]更便利: 口服或皮下给药,减少患者负担[499]更可及: 通过生物仿制药、成本优化,让更多患者获益[500] AD的完全治愈之路依然漫长,但我们已经迈出了历史性的第一步。科学界、制药工业、监管机构和患者群体的共同努力,将继续推动这一领域向前发展[501][502]。文档完成声明本综合报告涵盖了截至2025年1月的阿尔茨海默病药物治疗全景: ✅ 4个传统药物完整分析 ✅ 3个抗Aβ单抗(aducanumab, lecanemab, donanemab)深度对比 ✅ 10+个在研Aβ/tau靶向疗法进展追踪 ✅ 15+个非靶向机制创新疗法机制解析 ✅ 502篇参考文献完整引用核心结论: Lecanemab和donanemab是首次证明能够减缓AD认知衰退的疾病修饰疗法(27-36%减缓) 抗tau抗体(E2814, bepranemab)和tau ASO(BIIB080)代表下一代希望非靶向机制(神经炎症、代谢、肠道菌群)提供互补治疗路径未来将走向更早期干预+多靶点联合+精准医疗的综合策略数据更新: 本文档反映2025年1月的最新临床试验进展,部分Phase 3试验结果将在2025-2026年公布。参考文献 [1] Watkins PB, et al. 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Evaluate Pharma. https://www.evaluate.com/vantage/articles/analysis/anti-amyloid-competition-2024 附录:术语表与缩写缩写全称中文 AD Alzheimer's Disease 阿尔茨海默病 Aβ Amyloid-beta β-淀粉样蛋白 ADAS-Cog Alzheimer's Disease Assessment Scale-Cognitive subscale 阿尔茨海默病评估量表-认知部分 APOE Apolipoprotein E 载脂蛋白E ARIA Amyloid-Related Imaging Abnormalities 淀粉样蛋白相关影像异常 ARIA-E ARIA-Edema 淀粉样蛋白相关水肿 ARIA-H ARIA-Hemosiderin deposition 淀粉样蛋白相关微出血/含铁血黄素沉积 ASO Antisense Oligonucleotide 反义寡核苷酸 BACE β-site APP Cleaving Enzyme β分泌酶 BBB Blood-Brain Barrier 血脑屏障 CAA Cerebral Amyloid Angiopathy 脑淀粉样血管病 CDR-SB Clinical Dementia Rating-Sum of Boxes 临床痴呆评定量表-总和评分 ChEI Cholinesterase Inhibitor 胆碱酯酶抑制剂 CSF Cerebrospinal Fluid 脑脊液 EMA European Medicines Agency 欧洲药品管理局 FDA Food and Drug Administration 美国食品药品监督管理局 FDG-PET Fluorodeoxyglucose Positron Emission Tomography 氟脱氧葡萄糖正电子发射断层扫描 MCI Mild Cognitive Impairment 轻度认知障碍 MMSE Mini-Mental State Examination 简易精神状态检查 MRI Magnetic Resonance Imaging 磁共振成像 MTBR Microtubule-Binding Region 微管结合区 NFT Neurofibrillary Tangles 神经原纤维缠结 NMDA N-methyl-D-aspartate N-甲基-D-天冬氨酸 PET Positron Emission Tomography 正电子发射断层扫描 p-tau Phosphorylated tau 磷酸化tau蛋白 TREM2 Triggering Receptor Expressed on Myeloid cells 2 髓系细胞触发受体2 本文内容来自公开信息及研究文献，不代表临床建议。如需投稿、转载、商务合作后台留言，回复有一定延迟敬请谅解。辅助编辑：腾讯元宝or（GPT、Gemini、Claude等）

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RAGE406R：靶向 RAGE-DIAPH1 通路的糖尿病并发症防治

糖尿病及其并发症已构成全球性重大公共卫生挑战，全球患者总数超 5 亿，其中并发症是导致患者死亡与残疾的首要原因。传统降糖疗法虽能控制血糖水平，但难以阻止晚期糖基化终产物（AGEs）介导的组织损伤，约 40% 血糖控制达标的患者仍会进展为心血管疾病、肾功能衰竭或伤口愈合障碍等严重并发症。纽约大学朗格尼医学中心研究团队在《细胞化学生物学》发表的突破性研究，开发出小分子化合物 RAGE406R，通过特异性阻断 RAGE 受体与 DIAPH1 蛋白的相互作用，从分子源头切断炎症信号传导通路。动物实验证实，该化合物对 1 型和 2 型糖尿病模型均有效，可显著加速伤口愈合、减轻心肾组织损伤，且不影响血糖代谢。本文系统阐述 RAGE406R 的分子设计原理、作用机制、药理活性及临床转化潜力，深入分析其在糖尿病并发症精准治疗中的创新价值，同时探讨当前糖尿病并发症治疗的困境与多维度解决方案的发展趋势，为代谢性疾病的靶向药物研发提供科学参考。一、引言：糖尿病并发症的治疗困境与突破契机 1.1 全球糖尿病流行现状与并发症负担糖尿病作为一种以高血糖为核心特征的慢性代谢性疾病，已呈现全球爆发态势。国际糖尿病联盟（IDF）数据显示，2024 年全球 20-79 岁人群糖尿病患病率达 6.1%，患者总数突破 5.37 亿，预计 2045 年将增至 7.83 亿。中国作为糖尿病负担最重的国家，患者规模已达 1.41 亿，其中仅 36.7% 的患者血糖控制达标（HbA1c＜7%），超过半数患者面临并发症高风险。糖尿病并发症涵盖微血管病变（肾病、视网膜病变、神经病变）和大血管病变（心血管疾病、脑血管疾病），以及伤口愈合障碍等，其病理本质是长期高血糖诱导的 AGEs 蓄积引发的全身性炎症反应与组织损伤。据统计，糖尿病患者心血管疾病发生率是非糖尿病人群的 2-4 倍，糖尿病肾病占终末期肾病病因的 40% 以上，2 型糖尿病男性患者中 52% 存在勃起功能障碍等神经血管并发症，这些并发症导致的医疗支出占糖尿病总医疗费用的 60%-80%。 1.2 传统治疗策略的局限性与机制瓶颈当前临床糖尿病治疗以血糖控制为核心，主要包括胰岛素替代疗法、口服降糖药（如二甲双胍、磺脲类）及新型降糖药物（GLP-1 受体激动剂、SGLT2 抑制剂）。尽管这些药物能有效降低血糖，部分新型药物还显示出一定的心血管保护作用，但均无法从根本上阻断并发症的发生发展。其核心原因在于，糖尿病并发症的驱动机制并非高血糖本身，而是高血糖诱导的 AGEs 与细胞表面受体结合引发的下游病理级联反应。即使血糖控制在理想范围，体内已形成的 AGEs 仍会持续积累，通过非酶促糖基化修饰细胞内蛋白质、脂质和核酸，破坏组织细胞功能。此外，糖尿病患者常存在 "代谢记忆" 现象，早期血糖波动导致的分子损伤会持续存在，即使后续血糖得到控制，并发症风险仍显著升高。这一机制瓶颈导致传统降糖疗法难以满足临床对并发症防治的迫切需求，亟需开发针对并发症发病分子机制的靶向干预策略。 1.3 RAGE-DIAPH1 通路：并发症防治的关键靶点纽约大学格罗斯曼医学院安・玛丽・施密特教授团队长期致力于糖尿病并发症分子机制研究，其前期工作已明确 AGEs 受体（RAGE）介导的信号通路是并发症发生的核心枢纽。RAGE 作为免疫球蛋白超家族成员，广泛表达于内皮细胞、巨噬细胞、心肌细胞、肾系膜细胞等多种组织细胞表面。当 AGEs 与 RAGE 结合后，会诱导受体构象改变，使其胞内结构域与下游效应蛋白 DIAPH1（成束蛋白同源物 1）结合，进而激活肌动蛋白细胞骨架重排，启动 NF-κB 等炎症通路，促进促炎因子（IL-1β、TNF-α）和趋化因子（CCL2）释放，最终导致组织损伤与修复功能障碍。这一通路的发现为并发症治疗提供了全新靶点，而 RAGE406R 的开发正是针对这一关键分子相互作用的精准干预，标志着糖尿病治疗从 "血糖控制" 向 "损伤阻断" 的范式转变。二、RAGE406R 的分子设计与优化 2.1 靶点验证与先导化合物筛选 RAGE-DIAPH1 相互作用作为并发症发病的关键节点，其特异性阻断具有重要治疗价值。研究团队首先通过免疫共沉淀、荧光共振能量转移（FRET）等技术，验证了 AGEs 诱导下 RAGE 与 DIAPH1 的特异性结合，且这一结合在糖尿病患者组织样本中显著增强。为筛选能够阻断该相互作用的小分子化合物，团队构建了基于荧光偏振的高通量筛选体系，对包含 58000 个化合物的化学库进行系统性筛选。筛选标准包括：对 RAGE-DIAPH1 结合的抑制活性（IC50＜10μM）、对细胞的低毒性（CC50＞100μM）及良好的水溶性与细胞膜穿透性。通过多轮筛选与验证，最终获得先导化合物 RAGE229，该化合物在体外实验中显示出较强的结合抑制活性（IC50=7.3μM），并能显著抑制 AGEs 诱导的炎症因子释放。 2.2 结构优化与安全性提升尽管 RAGE229 具有良好的药理活性，但在 Ames 试验（沙门氏菌回复突变试验）中发现其存在潜在致突变风险，推测与分子结构中的芳香胺基团相关。为解决这一安全性问题，纽约州立大学奥尔巴尼分校化学系团队采用基于结构的药物设计策略，通过分子对接技术模拟 RAGE 与 DIAPH1 的结合口袋，对 RAGE229 进行结构修饰：去除芳香胺等潜在致癌基团，引入亲水性杂环结构以改善水溶性；优化分子骨架的空间构象，增强与 RAGE 胞内结构域的结合特异性。经过多轮结构优化与活性筛选，最终获得优化产物 RAGE406R。该化合物保留了对 RAGE-DIAPH1 结合的高效抑制活性（IC50=5.8μM），同时在 Ames 试验、染色体畸变试验等标准安全性评估中均显示阴性结果，细胞毒性显著降低（CC50=237μM），为后续临床转化奠定了安全基础。 2.3 分子作用机制的验证通过表面等离子体共振（SPR）技术检测证实，RAGE406R 与 RAGE 胞内结构域的结合常数（KD）为 3.2μM，显著高于 DIAPH1 与 RAGE 的结合常数（KD=12.7μM），表明其具有更强的结合亲和力。竞争结合实验显示，RAGE406R 通过竞争性占据 DIAPH1 在 RAGE 上的结合位点，阻止两者相互作用，且这一竞争作用具有浓度依赖性。免疫荧光实验进一步证实，在 AGEs 刺激的内皮细胞中，RAGE406R 处理可显著减少 RAGE 与 DIAPH1 的共定位现象，同时抑制肌动蛋白丝的异常聚集。Western blot 分析显示，RAGE406R 能有效阻断 AGEs 诱导的 NF-κB 磷酸化与核转移，减少 IL-1β、TNF-α、CCL2 等炎症因子的表达，而对 RAGE 的正常生理功能无明显影响，体现了良好的作用特异性。三、RAGE406R 的药理活性与作用机制 3.1 对糖尿病伤口愈合的促进作用糖尿病伤口愈合障碍的核心病理机制是炎症微环境失衡与组织修复能力下降。研究团队采用两种糖尿病动物模型进行验证：1 型糖尿病（链脲佐菌素诱导）小鼠与 2 型糖尿病（db/db）肥胖小鼠。在伤口愈合实验中，将 RAGE406R（10μM）制成外用凝胶涂抹于小鼠背部全层皮肤缺损伤口，每日 1 次，连续观察 14 天。结果显示，与对照组相比，RAGE406R 治疗组 1 型糖尿病小鼠伤口愈合时间缩短 31%，2 型糖尿病小鼠伤口愈合时间缩短 27%，且雌雄小鼠均表现出显著疗效。组织学分析显示，治疗组伤口处胶原蛋白沉积更规律，Ⅰ 型 /Ⅲ 型胶原蛋白比例趋于正常，新生血管密度增加 42%，表皮再生速度加快 35%。其促进愈合的机制主要通过重塑免疫微环境实现：RAGE406R 显著降低伤口局部 CCL2 水平（下降 58%），减少过度促炎型巨噬细胞（M1 型）聚集；同时促进巨噬细胞向修复表型（M2 型）转化，使 M2/M1 比例提升 2.3 倍。M2 型巨噬细胞分泌的转化生长因子 β（TGF-β）、血管内皮生长因子（VEGF）等细胞因子水平显著升高，分别促进成纤维细胞增殖与血管新生，加速伤口愈合进程。这一作用与中国科学院研究证实的 "糖尿病伤口中 REG3A 表达抑制导致炎症失控" 形成互补，通过调节趋化因子信号纠正炎症失衡。 3.2 对心肾并发症的保护作用糖尿病肾病与心血管疾病是导致患者死亡的主要并发症，其病理基础均与 AGEs-RAGE 介导的炎症和氧化应激相关。在慢性糖尿病小鼠模型（链脲佐菌素诱导后持续 16 周）中，腹腔注射 RAGE406R（10mg/kg，每周 3 次）连续治疗 8 周后，小鼠尿白蛋白 / 肌酐比值下降 47%，肾小球系膜区扩张程度显著减轻，足细胞损伤标志物 nephrin 的表达水平提升 53%。肾脏组织氧化应激指标检测显示，超氧化物歧化酶（SOD）活性提升 38%，丙二醛（MDA）含量下降 42%，表明 RAGE406R 能有效抑制肾脏组织的氧化应激损伤。心血管保护方面，RAGE406R 治疗显著降低糖尿病小鼠的心肌肥厚指数（下降 29%），改善左心室舒张功能。心肌组织病理学分析显示，心肌纤维化程度减轻，炎症细胞浸润减少，血管平滑肌细胞异常增殖受到抑制。机制研究表明，RAGE406R 通过阻断 RAGE-DIAPH1 通路，抑制心肌细胞与血管内皮细胞的炎症反应，减少活性氧（ROS）生成，从而减轻心肌重构与血管损伤。这一结果与 SGLT2 抑制剂等新型降糖药的心血管保护作用形成协同，为联合治疗提供了可能。 3.3 作用特异性与普适性 RAGE406R 的显著优势在于其作用的高度特异性与疗效普适性。与传统药物不同，该化合物不影响胰岛素分泌、葡萄糖转运等血糖调节相关通路，在动物实验中对正常小鼠和糖尿病小鼠的血糖水平均无明显影响，避免了降糖药物可能导致的低血糖风险。同时，其对 1 型和 2 型糖尿病模型均有效，突破了当前多数创新药物（如 GLP-1 受体激动剂）主要适用于 2 型糖尿病的局限，为治疗选择有限的 1 型糖尿病患者提供了新的希望。进一步研究显示，RAGE406R 对 RAGE 的其他配体（如 S100 蛋白家族）介导的信号通路无明显影响，表明其不会干扰 RAGE 在免疫调节、组织发育等方面的正常生理功能，降低了脱靶效应风险。这种高度特异性源于其针对 RAGE 胞内结构域与 DIAPH1 结合位点的精准设计，区别于其他靶向 RAGE 的药物（多阻断配体与 RAGE 胞外域结合），具有更好的安全性与耐受性潜力。四、糖尿病并发症治疗的技术格局与 RAGE406R 的创新价值 4.1 现有并发症治疗药物的分类与局限当前糖尿病并发症治疗药物主要分为三类：一是降糖药物的延伸应用，如 SGLT2 抑制剂（恩格列净）、GLP-1 受体激动剂（司美格鲁肽），虽显示出心血管与肾脏保护作用，但主要适用于 2 型糖尿病，且对已发生的组织损伤修复效果有限；二是对症治疗药物，如用于糖尿病神经病变的普瑞巴林、用于勃起功能障碍的 PDE5 抑制剂（西地那非），仅能缓解症状，无法阻断病理进程，且糖尿病患者中存在 "高血药浓度 - 低组织利用率" 的矛盾，疗效不佳且不良反应风险增加；三是抗氧化与抗炎药物，如 α- 硫辛酸、维生素 E 等，作用机制广泛，特异性差，临床疗效有限。此外，还有针对 AGEs 形成的抑制剂（如氨基胍），但因安全性问题未能上市；俄罗斯科学家开发的新型化合物通过与葡萄糖羰基反应减少 AGEs 生成，代表了另一治疗思路，但仍处于早期研究阶段。这些药物的局限凸显了 RAGE406R 的创新价值：通过精准靶向并发症发病的核心通路，实现病因治疗；适用于不同类型糖尿病；不影响血糖代谢，可与现有降糖药物联合使用。 4.2 与其他 RAGE 靶向药物的对比优势 RAGE 作为并发症治疗的重要靶点，已有多种药物处于研发阶段，但作用策略存在显著差异。多数在研药物（如 FPS-ZM1、Azeliragon）通过结合 RAGE 胞外域，阻断 AGEs 等配体与受体的结合，从而抑制下游信号传导。这类药物的局限在于可能影响 RAGE 的正常生理配体结合，导致脱靶效应；且 RAGE 胞外域存在多种配体结合位点，难以实现完全特异性阻断。 RAGE406R 则采用独特的作用策略，针对 RAGE 胞内域与 DIAPH1 的相互作用进行阻断，仅抑制 AGEs 诱导的病理性信号传导，不影响 RAGE 与其他配体的正常结合及生理功能。这种下游靶向策略具有更高的特异性，降低了对机体正常生理过程的干扰。此外，RAGE406R 作为小分子化合物，相比抗体类药物具有分子量小、细胞膜穿透性强、生产成本低、可口服给药等优势，显著提升患者依从性，更适合慢性并发症的长期治疗。 4.3 联合治疗的潜力与应用前景 RAGE406R 的作用机制与现有降糖药物完全互补，为联合治疗提供了广阔空间。临床前研究显示，RAGE406R 与二甲双胍、司美格鲁肽等药物联合使用时，在改善糖尿病小鼠心肾功能、促进伤口愈合方面表现出协同效应，且未增加不良反应风险。这种联合策略可实现 "血糖控制 + 损伤阻断" 的双重目标，尤其适用于血糖控制不佳或已出现早期并发症的患者。此外，RAGE 通路不仅参与糖尿病并发症，还在阿尔茨海默病、动脉粥样硬化、肿瘤等疾病的发展中发挥作用。RAGE406R 的成功开发为这些疾病的治疗提供了借鉴，未来有望通过结构修饰开发针对不同疾病的靶向药物，拓展其应用范围。五、临床转化挑战与未来发展方向 5.1 临床转化的关键挑战尽管 RAGE406R 在动物实验中取得了显著成果，但从临床前研究到人体应用仍面临多重挑战。首先，药物代谢动力学特性需要进一步优化，包括提高口服生物利用度、延长半衰期、优化组织分布，以确保在人体中达到有效治疗浓度。其次，需要开展全面的毒理学研究，包括长期毒性、生殖毒性、致癌性等，明确其安全剂量范围与潜在不良反应。药物开发的历史数据显示，约 30% 的候选药物因临床前毒性问题终止研发，因此全面的安全性评估至关重要。第三，临床试验设计面临挑战。糖尿病并发症具有多样性、进展缓慢等特点，需要选择合适的临床终点指标。例如，针对糖尿病肾病的临床试验可选择尿白蛋白 / 肌酐比值、估算肾小球滤过率（eGFR）作为主要终点；针对伤口愈合的试验可选择完全愈合时间作为主要终点。同时，需考虑患者的异质性，包括糖尿病类型、病程、并发症严重程度等，确保临床试验结果的可靠性与适用性。此外，药物研发还面临资金投入大、研发周期长等问题，需要学术机构与制药企业合作推进。 5.2 技术优化与发展方向为推动 RAGE406R 的临床转化，未来需从多个方面进行技术优化。在药物剂型方面，可开发口服制剂（如胶囊、片剂）、局部给药制剂（如伤口凝胶、滴眼液）、缓释制剂等，满足不同并发症的治疗需求。例如，针对糖尿病足溃疡可开发外用缓释凝胶，延长药物在伤口局部的作用时间；针对心肾并发症可开发口服制剂，实现全身给药。在作用靶点方面，可通过基因编辑技术（如 CRISPR-Cas9）进一步验证 RAGE-DIAPH1 通路在人体并发症中的作用，明确药物的适用人群，实现精准医疗。同时，可探索 RAGE406R 与其他靶点药物的联合使用，如与抗氧化剂、抗炎因子、干细胞疗法等结合，进一步提升治疗效果。中国批准的首个再生胰岛注射液临床试验为 1 型糖尿病治疗带来了新希望，未来可探索 RAGE406R 与干细胞疗法联合，在修复胰岛功能的同时阻断并发症进展。在诊断与监测方面，可开发基于 RAGE-DIAPH1 结合水平的生物标志物，用于并发症的早期诊断、病情监测与疗效评估。例如，通过检测血液中可溶性 RAGE-DIAPH1 复合物水平，预测患者并发症风险，指导治疗方案选择。 5.3 伦理与公共卫生意义 RAGE406R 的研发与应用具有重要的伦理与公共卫生价值。从伦理角度看，该药物为糖尿病患者提供了更安全、有效的治疗选择，尤其关注到 1 型糖尿病患者等弱势群体的治疗需求，体现了医疗公平性原则。同时，其精准靶向机制减少了不良反应，符合 "以人为本" 的医疗伦理理念。从公共卫生角度看，若 RAGE406R 成功上市，将显著降低糖尿病并发症的发生率与严重程度，减少慢性伤口、肾透析、心血管手术等带来的医疗负担。全球每年因糖尿病并发症导致的医疗支出超过数千亿美元，有效防治并发症可节约大量医疗资源，同时提高患者生活质量，延长健康寿命。此外，该药物的研发模式（基础研究 - 靶点发现 - 高通量筛选 - 结构优化 - 临床前验证）为其他代谢性疾病的药物开发提供了可借鉴的范式，推动精准医学在慢性病治疗中的应用。六、结论纽约大学研究团队开发的小分子化合物 RAGE406R，通过特异性阻断 RAGE-DIAPH1 相互作用，为糖尿病并发症治疗提供了全新路径。其独特的分子设计与优化策略，实现了高活性与高安全性的统一；动物实验证实其在促进伤口愈合、保护心肾功能方面具有显著疗效，且适用于 1 型和 2 型糖尿病，展现出广阔的临床应用前景。RAGE406R 的突破不仅打破了传统降糖疗法的局限，更标志着糖尿病治疗进入 "靶向损伤阻断" 的精准医学时代。尽管该药物仍面临临床转化的多重挑战，但随着药物代谢动力学优化、毒理学研究深入与临床试验的推进，有望在未来 5-8 年内实现临床应用。同时，其作用机制的深入研究与技术拓展，将为阿尔茨海默病、动脉粥样硬化等其他与 RAGE 通路相关疾病的治疗提供新的思路。在精准医学理念的指导下，未来糖尿病治疗将形成 "血糖控制 + 并发症阻断 + 康复治疗" 的多维度体系，为全球 5 亿糖尿病患者带来新的希望，推动糖尿病防治水平的整体提升。

突破性疗法临床结果

2025-11-16

·生信文献解读

IF=11.2！吃透“孟德尔随机化”红利期，看浙大/杭师大团队这篇《Genome Medicine》如何用MR+多组学，发双一区

一段话总结今天继续给大家解读公共数据联合孟德尔和多组学的纯生信文章，这篇文章是浙大附属邵逸夫医院团队今年10月发表在《Genome Medicine》上的，影响因子11.2分，它用大型公共数据库+多组学+孟德尔这一当前特别火的套路，把蛋白质、基因、代谢物一口气全分析了，直接把衰老研究拔高了一个维度。关键是，这个思路咱们要复刻也并不难。大家都知道，单纯做个孟德尔随机化的文章现在基本上很难发出去，但是不可否认，孟德尔随机化分析是一种很好的分析方法，用它做因果推断会比普通的相关分析研究的更深入，所以用它作为文章的一个重要组成部分，联合别的，比如多组学，就是可以让研究做的更全面更深入，这也是当前用公共数据库的数据，联合孟德尔和多组学还是很受高分期刊亲耐的原因。对于自己没有数据，又想把文章发出去，甚至还想发高分一点的期刊，这个套路非常值得借鉴，想看看自己研究方向是不是也是适合用这个套路的朋友，欢迎在评论区留言~ 该研究针对多维衰老表型的蛋白质组学景观尚未充分表征的研究缺口，利用 UK Biobank 队列的 2920 种血浆蛋白质组生物标志物及 48728 名参与者数据，结合两样本孟德尔随机化（MR）、多变量线性回归等方法，系统探究了血浆蛋白质组与 KDM-BA 加速、PhenoAge 加速、衰弱指数、白细胞端粒长度（LTL）及健康跨度等多维衰老表型的因果关系与表型关联，并通过 FinnGen 队列、父母寿命 GWAS 数据等进行验证，同时整合多组学数据解析其生物学功能、遗传机制及代谢通路，最终鉴定出 71 种与多维衰老表型相关的独特血浆蛋白质，其中 12 种具有药物靶向潜力，为个性化衰老监测及衰老相关疾病的治疗策略提供了重要依据。所有解读的文献原文都给大家准备好了点击下方卡片↓↓回复【原文】领走文献介绍中文标题：多维衰老表型的蛋白质组学景观发表期刊：Genome Medicine 发表时间：2025 年10月影响因子：11.2 研究背景衰老为多系统复杂过程，单一生物标志物难以全面准确反映个体衰老全貌，需通过多维指标（如生物年龄加速、衰弱指数、端粒长度、健康跨度等）综合量化。血浆蛋白质作为健康与疾病状态的综合反映，是潜在的生物标志物和治疗靶点，蛋白质稳态丧失更是衰老的核心特征之一。尽管已有研究鉴定出部分与衰老相关的蛋白质标志物，但针对多维衰老表型的完整蛋白质组学景观仍不明确，且现有研究多聚焦于单一衰老维度，缺乏对蛋白质组上游调控因子和下游效应的系统阐释，亟需通过大规模研究填补这一空白。数据来源队列数据：主要来自 UK Biobank（48728 名参与者，含蛋白质组、基因组、代谢组及多维衰老表型数据），验证数据来自 FinnGen 队列（619 名芬兰参与者的蛋白质组遗传关联数据）。蛋白质组数据：UK Biobank Pharma Proteomics Project（UKBPPP）的 2920 种血浆蛋白质（经 Olink Explore 3072 平台检测，排除缺失率超 30% 的蛋白质后获得）。基因组数据：自主开展的多维衰老表型 GWAS 数据（UK Biobank 非重叠样本，样本量 311471-367873 不等）、UKBPPP 的血浆蛋白质 GWAS 汇总数据、父母寿命 GWAS 数据（约 100 万欧洲血统参与者）。代谢组数据：UK Biobank 中 280000 名参与者的靶向核磁共振（NMR）代谢组学数据，含 249 种代谢指标。临床数据：UK Biobank 的住院记录（ICD-10 编码）、自我报告的健康信息等，用于表型全关联分析（PheWAS）。研究框架及详细技术路线图研究步骤及结果展示 1. 遗传与表型关联分析结果 MR 分析：鉴定出 17、37、12、18、1 种蛋白质分别与 KDM-BA 加速、PhenoAge 加速、衰弱指数、LTL、健康跨度存在因果关联（Bonferroni 校正 p<0.05）；FDR 校正后共获得 180 种独特蛋白质，Bonferroni 校正后为 71 种。验证结果：FinnGen 队列中复制到 4-5 种蛋白质与对应衰老表型的关联；12 种蛋白质在父母寿命 GWAS 中显示一致的方向效应且达到名义显著性（p<0.05）；HLA-DRA 是唯一经纵向健康 span 数据验证的蛋白质。表型关联：2186、2152、1459、668、545 种蛋白质分别与 KDM-BA 加速、PhenoAge 加速、衰弱指数、LTL、健康跨度存在显著表型关联（Bonferroni 校正 p<0.05），其中 GDF15 与衰弱指数、健康跨度的关联最强。2. 生物学功能分析结果富集通路：71 种蛋白质显著富集于免疫反应调控、细胞黏附调控等通路，细胞组分层面富集于 MHC 蛋白质复合物。 PPI 网络：核心节点蛋白质为 NFKB1（炎症调控关键因子）、CXCL8（促炎趋化因子）、APOE（脂质转运与免疫相关蛋白）。组织与细胞特异性：蛋白质编码基因仅在肝脏组织中显示差异表达，66 种基因在肝脏 17 种细胞类型中存在细胞特异性富集（如 APOE 富集于巨噬细胞，LEPR 富集于肝细胞）。3. PheWAS 与药物靶向分析结果 PheWAS：64/71 种蛋白质与至少 1 种临床表型显著关联，共 2716 对蛋白质 - 疾病关联（3.3%），其中 2447 对为有害效应，269 对为有益效应（如 ASGR1 与 202 种健康状况相关）。药物靶向：12/71 种蛋白质已进入药物研发阶段，如 AGER 靶向药物 AZELIRAGON 用于阿尔茨海默病治疗，NFKB1 抑制剂 EDASALONEXENT 用于 2 型糖尿病治疗。4. 遗传与代谢机制结果遗传机制：22 种遗传变异通过调控蛋白质丰度影响衰老（如 APOE 的 rs429358 变异），26 对蛋白质 - 衰老表型存在共定位证据（PP.H4≥0.80）。代谢介导：853 种代谢物 - 衰老表型关联显著，12577 种蛋白质 - 代谢物关联显著，9356 条代谢通路介导蛋白质与衰老表型的关联（如 ASGR1 对 PhenoAge 加速的影响 29% 由肌酐介导）。研究结论该研究通过大规模多组学整合分析，首次系统描绘了多维衰老表型的蛋白质组学景观，鉴定出 71 种与衰老密切相关的独特血浆蛋白质，其中 12 种具有可靠验证证据及药物靶向潜力。研究证实炎症反应和细胞衰老是衰老过程中的核心生物学功能，肝脏组织及相关细胞类型在衰老调控中具有重要作用，22 种遗传变异和多种代谢通路参与蛋白质介导的衰老过程。这些发现填补了多维衰老蛋白质组学研究的空白，为个性化衰老监测、抗衰老干预及衰老相关疾病的靶向治疗提供了关键的生物标志物和分子机制基础。顺着这个思路，我们去做一些相关的复刻也并不难，例如，将“衰老”换成“代谢综合征”或“神经退行性疾病”，构建多维表型（如血糖、血脂、肝肾功能、认知评分）。数据就用UKB、FinnGen、CHARLS、NHANES中具备蛋白质组数据的队列。分析流程，筛选与目标疾病相关的蛋白质（MR + 表型关联）；整合基因组、代谢组进行中介分析；构建PPI网络，识别核心蛋白；评估药物靶点潜力（OpenTargets）。或者深挖特定人群或组织特异性，比如聚焦“肝脏衰老”，利用单细胞数据（如本文中的人类肝细胞数据）分析蛋白在肝细胞、巨噬细胞等中的特异性表达。针对某一人群（如女性、老年人、糖尿病患者）分析蛋白-衰老关联的异质性。还可以结合转录组、表观组，探索蛋白表达的调控机制。再就是，升级中介分析，引入更精准的机制指标，比如在已有代谢物（如GlycA、LDL）基础上，加入细胞因子（IL-6, TNF-α）、衰老相关分泌表型因子等，构建更精细的“蛋白-炎症-衰老”通路。对这些思路感兴趣，想深入了解的朋友，也可以咨询我们的一对一服务~ 想要快速产出高质量研究成果的朋友，欢迎咨询「医嘉研临床研究1V1指导」！我们将从选题方向沟通、数据收集、统计分析、写作指导、专家评审、语言编辑、投稿指导为您提供全方位指导！ END 医嘉研专注于提供医学科研服务，不论您是需要发SCI还是国内核心，都可以联系我们！主要方向如下： Meta分析经典meta，网状meta，预测模型meta等等，医护全领域各类meta分析！临床研究 MIMIC数据库挖掘、NHANES数据库、GBD数据库、CHARLS数据库、临床真实数据（已有数据或制定数据收集方案）生信分析转录组、单细胞测序、蛋白组、基因组、代谢组、孟德尔随机化、网络药理学、分子对接、多组学+机器学习等各类生信分析指导服务！扫码了解更多内容医嘉研专注于医学科研1V1指导

信使RNA

100 项与 Azeliragon 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11147	-	-	DB12689

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
新型冠状病毒感染	临床3期	美国	Cantex Pharmaceuticals, Inc.	2023-09-27
阿尔茨海默症	临床3期	美国	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	澳大利亚	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	加拿大	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	爱尔兰	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	新西兰	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	南非	vTv Therapeutics, Inc.	2015-04-01
阿尔茨海默症	临床3期	英国	vTv Therapeutics, Inc.	2015-04-01
胶质母细胞瘤，IDH野生型	临床2期	美国	Cantex Pharmaceuticals, Inc.	2023-09-12
多形性胶质母细胞瘤	临床2期	西班牙	Cantex Pharmaceuticals, Inc.	2023-09-05

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05635734 (CAN-201 NDG, ASCO2025)	临床1/2期	胶质母细胞瘤 IDH wild-type \| MGMT methylation	20	Azeliragon 5 mg/day	憲膚鑰鹹鹹築選鑰選醖(鏇遞獵繭顧構製願繭觸) = 構構繭遞鏇獵選鹽鹽窪醖構餘獵壓夢糧鬱齋憲 (夢壓蓋選壓膚構廠艱製, 9.4 ~ NR) 更多	积极	2025-05-30
				Azeliragon 10 mg/day	製艱鹽醖憲範願膚憲鏇(窪襯餘蓋廠選繭艱壓鏇) = 蓋觸構鏇繭齋窪鑰齋範選獵憲鬱襯鏇製製構積 (築觸餘夢簾艱憲衊鹹壓, 6.2 ~ NR)
NCT05789589 (ADORATION, ASCO2025)	临床1/2期	脑转移瘤	6	Azeliragon + SRS + LD	鏇選襯衊範簾夢夢齋膚(簾膚餘遞齋夢糧餘構獵) = 淵糧築艱衊選壓範獵觸襯膚鹹顧鑰糧餘壓壓鹽 (齋壓糧獵願繭製淵範鹽 )	积极	2025-05-30
				Azeliragon + SRS	鏇選襯衊範簾夢夢齋膚(簾膚餘遞齋夢糧餘構獵) = 膚築製願壓網淵製積選襯膚鹹顧鑰糧餘壓壓鹽 (齋壓糧獵願繭製淵範鹽 )
NCT05986851 (CTIM-26, SNO2024)	临床2期	胶质母细胞瘤 MGMT-unmethylated	30	Azeliragon 20 mg	鹽艱築獵築獵網蓋鹽膚(鹹醖網觸範鬱鹹廠顧鹹) = grade 1 獵衊觸遞糧鹹淵鏇鹽鏇 (範鬱艱廠廠淵鏇選鏇鏇 ) 更多	积极	2024-11-11
NCT05635734 (CAN-201 NDG, ESMO2024) 人工标引	临床1/2期	胶质母细胞瘤一线 IDH Family Wildtype	12	Azeliragon 5 mg/day	獵築襯蓋鏇齋鹹製壓築(憲艱範範鹹選艱製獵憲) = 構憲願衊膚觸獵窪遞糧憲艱齋願願獵憲襯糧壓 (繭構衊觸獵鏇遞鑰範鹽 ) 更多	积极	2024-09-15
				Azeliragon 10 mg/day	獵築襯蓋鏇齋鹹製壓築(憲艱範範鹹選艱製獵憲) = 膚獵鬱憲窪壓蓋餘夢鬱憲艱齋願願獵憲襯糧壓 (繭構衊觸獵鏇遞鑰範鹽 ) 更多
NCT03980730 (Elevage, CTgov)	临床2期	阿尔茨海默症 \| 葡萄糖耐受不良	43	Azeliragon (Azeliragon)	鬱淵觸蓋願網願獵鏇遞(憲淵觸壓鏇淵願鹹築憲) = 淵衊構齋簾築鏇鑰獵範夢淵襯遞齋衊廠憲壓醖 (夢醖簾餘網積範淵蓋積, 0.82) 更多	-	2022-01-21
				Placebo (Placebo)	鬱淵觸蓋願網願獵鏇遞(憲淵觸壓鏇淵願鹹築憲) = 襯鬱簾醖窪艱願鬱襯憲夢淵襯遞齋衊廠憲壓醖 (夢醖簾餘網積範淵蓋積, 0.69) 更多
NCT02916056 (CTgov)	临床3期	阿尔茨海默症	297	Azeliragon 5mg	構獵淵製醖顧糧襯構廠 = 範鏇餘窪衊窪範廠築網遞衊憲膚顧廠醖遞壓憲 (簾衊鹹顧窪選選壓製膚, 獵鹽夢顧窪獵衊夢襯觸 ~ 醖顧齋衊衊繭蓋選鏇鹽) 更多	-	2021-06-01
NCT02080364 (STEADFAST, CTgov)	临床3期	阿尔茨海默症	880	Azeliragon (Azeliragon 5mg)	範鏇範壓鹹積襯壓顧願(構蓋觸膚願觸鬱製齋壓) = 構蓋衊醖齋積蓋觸鬱鏇廠鑰淵範蓋餘鹽醖鑰顧 (築壓網選願顧繭廠願網, 0.001) 更多	-	2021-05-07
				Placebo (Placebo)	範鏇範壓鹹積襯壓顧願(構蓋觸膚願觸鬱製齋壓) = 觸範襯衊範鑰壓廠淵選廠鑰淵範蓋餘鹽醖鑰顧 (築壓網選願顧繭廠願網, 0.001) 更多
NCT02080364 (STEADFAST, BusinessWire) 人工标引	临床3期	阿尔茨海默症	800	Azeliragon	遞鏇窪簾遞醖築鹹鏇廠(餘構範夢艱鏇淵願鬱餘) = 網膚顧構製選繭夢繭壓蓋襯窪構鹹築鑰築鏇窪 (觸齋鑰遞夢齋獵構衊齋 ) 更多	不佳	2018-04-09
				Placebo	遞鏇窪簾遞醖築鹹鏇廠(餘構範夢艱鏇淵願鬱餘) = 鹹遞憲壓壓淵糧餘鏇繭蓋襯窪構鹹築鑰築鏇窪 (觸齋鑰遞夢齋獵構衊齋 ) 更多
NCT00566397 (CTAD2015)	临床3期	阿尔茨海默症	-	Azeliragon 20mg/day	衊遞鑰廠蓋鑰壓壓願齋(鹹鹽艱齋願鏇醖壓窪齋) = 鬱繭糧鏇齋鹽壓繭糧廠膚衊淵願窪廠繭醖壓網 (夢製積醖範夢鹽範鹽艱, 6.6) 更多	-	2015-11-04
				Azeliragon 5mg/day	衊遞鑰廠蓋鑰壓壓願齋(鹹鹽艱齋願鏇醖壓窪齋) = 蓋壓壓艱鬱衊糧簾鬱繭膚衊淵願窪廠繭醖壓網 (夢製積醖範夢鹽範鹽艱, 5.4) 更多