证据表明有因果关系,β淀粉样蛋白(Aβ)在阿尔茨海默病(AD)发病机制中的启动作用是重要的。然而,只有少数抗淀粉样蛋白药物在临床试验中显示出有意义的疗效.我们在长期试验中评估了具有阳性临床或生物标志物作用的抗淀粉样蛋白药物的统一特征,并分析了药理学特征如何决定其临床产品概况。四种具有近期批准潜力的药物符合这些标准:可注射抗体,aducanumab,gantenerumab,BAN2401和一种小分子口服药物,ALZ-801.Aducanumab和BAN2401对临床和生物标志物结果均显示出显着疗效;gantenerumab显示出显着的生物标志物效果,迄今为止,尚无临床疗效报道;ALZ-801在载脂蛋白E基因(APOE4)ε4等位基因纯合的高危患者群体中显示出明显的临床效果,并且剂量依赖性地保留了海马体积。我们探索了这些药物的药理特性,即对Aβ低聚物的选择性,血浆半衰期,大脑穿透,以及达到大脑暴露峰值的时间,确定他们的临床特征。这些药物共有的一个关键特征是它们能够参与神经毒性的可溶性Aβ寡聚体,尽管程度不同。Aducanumab和gantenerumab部分靶向寡聚体,虽然主要清除不溶性淀粉样蛋白斑块;BAN2401优先靶向可溶性原纤维(大寡聚体)而不是斑块;ALZ-801阻断寡聚体的形成而不与斑块结合。Aβ寡聚体的选择性程度和脑暴露驱动临床疗效的大小和开始,而斑块的清除与血管源性脑水肿有关。只有最高剂量的aducanumab和BAN2401显示适度的疗效,更高的剂量受到血管源性水肿风险增加的限制,尤其是在APOE4载体中。这些限制是可以避免的,通过选择性抑制Aβ寡聚体形成或阻断Aβ寡聚体毒性而不清除淀粉样蛋白斑块的小分子药物来提高疗效。最先进的选择性抗低聚物剂是ALZ-801,这是一种优化的曲米酸口服前药,这证明了在纯合APOE4/4AD受试者中的功效。ALZ-801在临床剂量下选择性和完全抑制Aβ42寡聚体的形成,没有血管源性水肿的证据,并将在纯合APOE4/4早期AD患者的3期试验中进行评估。除了临床措施,第三阶段试验将包括脑脊液,等离子体,和成像生物标志物,以进一步了解可溶性Aβ寡聚体在AD发病机理中的作用及其对疾病进展的影响。
The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer\'s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; 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 Aβ 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 Aβ 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 Aβ42 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 Aβ oligomers in the pathogenesis of AD and their impact on disease progression.