What have we learned from past failures of investigational drugs for Alzheimer’s disease?

Abstract

ABSTRACT Introduction 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. Area covered We reviewed literature on tau biology and anti-tau drugs 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. Expert opinion 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 minimise the potential introduction of major biases in the evaluation of the clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.