Department of Research & Development, Chiesi Farmaceutici, Parma, Italy.
CNS & Pain Department, TranScrip Ltd, Reading, UK.
Expert Opin Investig Drugs. 2021 Dec;30(12):1175-1182. doi: 10.1080/13543784.2021.2017881. Epub 2021 Dec 20.
In the last 15 years, huge efforts against Alzheimer's disease (AD) with drugs targeting β-amyloid (Aβ) and tau have produced poor clinical results. Aducanumab, a recently FDA-approved anti-Aβ monoclonal antibody has been greeted with distrust by most experts, hospitals and insurance companies for its level of efficacy and poor tolerability.
We reviewed literature on Alzheimer trials using PubMed, meeting abstracts and ClnicalTrials.gov and discuss what we can learn from past failures of investigational drugs for Alzheimer's disease, especially anti-Aβ and anti-tau drugs.
It is our opinion that previous failures of anti-AD drugs suggest that soluble Aβ and tau are not appropriate drug targets. In addition, pivotal clinical trials of future clinical candidates should avoid major protocol amendments and futility analyses. Study protocols should adopt better measures to protect study blinding and minimize the potential introduction of major biases in the evaluation of clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.
在过去的 15 年里，针对β-淀粉样蛋白（Aβ）和 tau 的药物在对抗阿尔茨海默病（AD）方面做出了巨大努力，但临床效果不佳。最近，美国食品和药物管理局（FDA）批准的抗 Aβ 单克隆抗体 aducanumab 因其疗效水平和较差的耐受性而受到大多数专家、医院和保险公司的不信任。
我们使用 PubMed、会议摘要和 ClnicalTrials.gov 回顾了关于阿尔茨海默病试验的文献，并讨论了我们可以从过去抗阿尔茨海默病药物的失败中吸取哪些教训，特别是针对 Aβ 和 tau 的药物。
我们认为，以前抗 AD 药物的失败表明可溶性 Aβ 和 tau 不是合适的药物靶点。此外，未来临床候选药物的关键性临床试验应避免主要方案修正案和无效性分析。研究方案应采用更好的措施来保护研究的盲法，并最大程度地减少在评估临床结果时引入主要偏差的可能性。最后，应寻求替代的生物学靶点，并采取更多针对 AD 中神经退行性变的多模式方法。
