Aducanumab、gantenerumab BAN2401, alz - 801第一批amyloid-targeting阿尔茨海默病药物与潜在近期批准。

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托拉尔M, Abushakra年代,嘿,是的,Porsteinsson, Sabbagh M

Aducanumab、gantenerumab BAN2401, alz - 801第一批amyloid-targeting阿尔茨海默病药物与潜在近期批准。

老年痴呆症Res。2020年8月12日,12 (1):95。doi: 10.1186 / s13195 - 020 - 00663 - w。

PubMed ID
32787971 (在PubMed
]
文摘

使役动词的证据表明,启动β淀粉样蛋白的作用(β淀粉状蛋白质)在阿尔茨海默病(AD)发病机理是十分可观的。然而,只有少数种抗体药物在临床试验中显示有意义的功效。我们评估的统一特征种抗体药物与积极的临床或生物标志物的影响在长期试验和分析了药理特点决定他们的临床产品资料。四个代理近期批准的潜力满足这些标准:注射抗体,aducanumab, gantenerumab, BAN2401,和一个小分子口服剂,alz - 801。Aducanumab BAN2401显示显著疗效临床和生物标志物的结果;gantenerumab显示显著的生物标志物的影响,没有临床疗效报道日期;和alz - 801显示显著临床疗效患者的高危人群epsilon4等位基因的纯合子的载脂蛋白E基因(APOE4)和剂量依赖性保护海马体积。我们探索这些药物的药理特性,即选择性β淀粉状蛋白质寡聚物,血浆半衰期,大脑渗透,和时间达到峰值大脑接触,确定其临床资料。这些代理共享的一个至关重要的特点是他们参与神经毒素可溶性β淀粉状蛋白质寡聚物的能力,尽管不同程度。Aducanumab和gantenerumab部分目标低聚物,而主要是清理不溶性淀粉样斑块; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Abeta oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Abeta oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Abeta42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Abeta oligomers in the pathogenesis of AD and their impact on disease progression.

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