Sabbagh Marwan N, Hendrix Suzanne, Harrison John E
Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
Pentara, Salt Lake City UT, USA.
Alzheimers Dement (N Y). 2019 Jan 10;5:13-19. doi: 10.1016/j.trci.2018.11.004. eCollection 2019.
Despite billions of dollars invested in clinical trials to develop novel therapeutics for Alzheimer's disease, no approved treatments have been developed in the past 15 years. In that span, new classes of drugs have been developed and tested, including monoclonal antibodies, γ-secretase modulators, γ-secretase inhibitors, BACE inhibitors, RAGE inhibitors, nicotinic agonists, 5HT6 antagonists, and others. The one constant for all of these clinical trials programs is the use of the ADAS-cog as the primary scale to determine efficacy. The question that needs to be considered is whether it is the target engagement of the drug or the clinical trial measure testing the efficacy. The FDA put out a new position statement in 2018 informing the field on possible considerations for demonstrating efficacy to open the path for approval. Here, we propose and comment on a variety of approaches that are alternatives to the ADAS for FDA-specified stage 3 and 4 Alzheimer's disease. These novel outcomes are being validated in current clinical trials and could be used as efficacy measures moving forward.
尽管在开发治疗阿尔茨海默病的新型疗法的临床试验中投入了数十亿美元，但在过去15年里，尚未开发出任何获批的治疗方法。在此期间，已经开发并测试了新的药物类别，包括单克隆抗体、γ-分泌酶调节剂、γ-分泌酶抑制剂、β-分泌酶抑制剂、晚期糖基化终末产物受体抑制剂、烟碱激动剂、5-羟色胺6拮抗剂等。所有这些临床试验项目的一个共同点是使用阿尔茨海默病评估量表认知部分（ADAS-cog）作为确定疗效的主要指标。需要考虑的问题是，这是药物的靶点参与情况还是测试疗效的临床试验指标。美国食品药品监督管理局（FDA）在2018年发布了一份新的立场声明，向该领域通报了在证明疗效以开辟批准途径方面可能需要考虑的因素。在此，我们提出并评论了多种方法，这些方法可替代FDA指定的3期和4期阿尔茨海默病的ADAS。这些新的结果正在当前的临床试验中得到验证，并可作为未来的疗效指标。
