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

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 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.

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 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.

KEYWORDS:

• Alzheimer’s disease
• clinical candidates
• biomarkers
• clinical testing
• β-amyloid
• tau
• neuroinflammation
• microglia
• microbiota
• multimodal

Article highlights

• Alzheimer’s disease (AD) is a progressive neurodegenerative disorder histologically characterized by the formation of brain amyloid plaques and neurofibrillary tangles.

• A long series of clinical failures has characterized the last 20 years of research for a disease-modifying agent. Only recently, an anti-β-amyloid monoclonal antibody (aducanumab) has been conditionally approved by the Food & Drug Administration based on its ability to reduce brain amyloid plaques in AD patients.

• The repeated failure of therapies aimed at attenuating the formation of brain amyloid plaques and neurofibrillary tangles and thus meaningfully modifying disease progression raises major questions about the validity of many aspects of drug development in this area, especially target selection.

• Although biomarkers for both early and late stages of AD are available, we need to identify biomarkers that correlate with individual patient response to drug treatment.

• Simple study design and clean conduct of clinical trials are essential to avoid undermining study blinding and increasing the risk of biased results.

• We must consider a broader, holistic approach to tackling AD that takes into account the complexity of disease biology.

Declaration of interests

Bruno P. Imbimbo is an employee at Chiesi Farmaceutici. He is listed among the inventors of a number of Chiesi Farmaceutici’s patents of anti-Alzheimer drugs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Disclosure statement

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This research did not receive funding or grants.