Clinical trials of new drugs for Alzheimer disease

Abstract

Alzheimer disease (AD) accounts for 60-70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies.In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov. We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.

Keywords: Alzheimer disease; Anti-amyloid; Anti-tau; Clinical trials of drugs; Cognitive enhancement; Neuroinflammation; Neuroprotection.

Fig. 1

On the basis of the amyloid hypothesis, the consequent events of pathophysiology and clinical course are amyloid accumulation, neuroinflammation, tau accumulation, brain metabolism dysfunction, brain atrophy, cognitive decline (from mild cognitive impairment to dementia), and dementia symptom development. New drugs should target at least one of these events

Fig. 2

Trend of phase 3 trials, 2017–2019, according to the event-related categories at ClincalTrials.gov. a Number of phase 3 trials. b Percentage of phase 3 trials

Fig. 3

Trends of phase 1 and phase 2 trials, 2017–2019, according to the event-related categories in ClincalTrials.gov. The percentages of phase 1 and phase 2 trials