Høilund-Carlsen Poul F, Revheim Mona-Elisabeth, Costa Tommaso, Kepp Kasper P, Castellani Rudolph J, Perry George, Alavi Abass, Barrio Jorge R
Department of Nuclear Medicine, Odense University Hospital, 5000 Odense C, Denmark.
Research Unit of Clinical Physiology and Nuclear Medicine, Department of Clinical Research, University of Southern Denmark, 5230 Odense M, Denmark.
Diagnostics (Basel). 2023 Jul 3;13(13):2254. doi: 10.3390/diagnostics13132254.
In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed by amyloid-PET and, in the case of lecanemab, also a presumption of limited clinical efficacy. Approval of the antibody donanemab is awaiting further data. However, published trial data indicate few, small and uncertain clinical benefits, below what is considered "clinically meaningful" and similar to the effect of conventional medication. Furthermore, a therapy-related decrease in the amyloid-PET signal may also reflect increased cell damage rather than simply "amyloid removal". This interpretation is more consistent with increased rates of amyloid-related imaging abnormalities and brain volume loss in treated patients, relative to placebo. We also challenge the current diagnostic criteria for AD based on amyloid-PET imaging biomarkers and recommend that future anti-AD therapy trials apply: (1) diagnosis of AD based on the co-occurrence of cognitive decline and decreased cerebral metabolism assessed by FDA-approved FDG-PET, (2) therapy efficacy determined by favorable effect on cognitive ability, cerebral metabolism by FDG-PET, and brain volumes by MRI, and (3) neuropathologic examination of all deaths occurring in these trials.
2021年6月，美国食品药品监督管理局（FDA）基于淀粉样蛋白PET评估的药物诱导的脑淀粉样β蛋白清除，加速批准了抗体药物阿杜卡努单抗；2023年1月，同样基于此，还加速批准了抗体药物乐卡奈单抗，就乐卡奈单抗而言，还基于有限临床疗效的推测。抗体药物多奈单抗的批准正在等待更多数据。然而，已发表的试验数据显示临床益处很少、规模小且不确定，低于被认为“具有临床意义”的水平，且与传统药物的效果相似。此外，淀粉样蛋白PET信号的治疗相关下降也可能反映细胞损伤增加，而不仅仅是“淀粉样蛋白清除”。这种解释与治疗患者中淀粉样蛋白相关影像学异常和脑容量损失发生率相对于安慰剂增加更为一致。我们还对基于淀粉样蛋白PET成像生物标志物的当前AD诊断标准提出质疑，并建议未来的抗AD治疗试验采用：（1）基于认知能力下降和FDA批准的FDG-PET评估的脑代谢降低共同出现来诊断AD；（2）通过对认知能力、FDG-PET脑代谢和MRI脑容量的有利影响来确定治疗效果；（3）对这些试验中发生的所有死亡病例进行神经病理学检查。
