Faculty of Health, Queensland University of Technology, Brisbane, Australia.
Expert Opin Pharmacother. 2019 Dec;20(17):2095-2099. doi: 10.1080/14656566.2019.1654998. Epub 2019 Aug 18.
: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in treating Alzheimer's disease. Aβ is formed by the cleavage of amyloid precursor protein by β-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aβ. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects.: Prior to completing EPOCH, APECS, which trialled verubecestat in prodromal Alzheimer's disease, was commenced. Like EPOCH, APECS was terminated early. In APECS, verubecestat 40 mg worsened cognition and increased adverse effects.: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aβ should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.
淀粉样蛋白-β（Aβ）级联假说认为，降低大脑中的 Aβ 水平将有益于治疗阿尔茨海默病。Aβ 是由淀粉样前体蛋白经β位淀粉样前体蛋白裂解酶（BACE1）切割形成的，BACE1 抑制剂维鲁贝克昔特被开发出来以降低大脑中的 Aβ 水平。然而，在维鲁贝克昔特治疗轻度至中度阿尔茨海默病的 EPOCH 试验中，它并没有带来益处，反而增加了不良反应。
在 EPOCH 试验之前，进行了维鲁贝克昔特治疗前驱期阿尔茨海默病的 APECS 试验，该试验也提前终止了。与 EPOCH 试验一样，APECS 也提前终止了。在 APECS 试验中，40mg 维鲁贝克昔特恶化了认知功能，并增加了不良反应。
在招募阿尔茨海默病临床试验的受试者时，所有受试者都应进行涉及 Aβ 测量的临床诊断，因为这可能有助于澄清研究结果。在我看来，如果在开始第 3 阶段之前完成了安全性和潜在疗效试验（第 2 阶段），那么 EPOCH 和 APECS 中维鲁贝克昔特的失败可能是可以避免的。在我看来，由于我们对阿尔茨海默病的潜在机制/病因了解甚少，这应该是研究的重点，而不是第 3 阶段的临床试验。
