Drug Development for Psychotropic, Cognitive-Enhancing, and Disease-Modifying Treatments for Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited available therapies. There is progress in developing treatments for neuropsychiatric indications in AD, including agitation, psychosis, apathy, and sleep disorders. Candidate therapies progress from nonclinical and animal assessment to trials in normal volunteers (phase 1), small phase-2 trials, and larger confirmatory phase-3 trials. Biomarkers play an increasingly important role in selecting participants, stratifying populations, demonstrating target engagement, supporting disease modification, and monitoring safety. There are currently 121 agents in clinical trials, including treatments for neuropsychiatric symptoms, cognition enhancement, and disease progression. There are 27 agents in phase-1 trials, 65 in phase-2 trials, and 29 in phase-3 trials. Most of the agents in trials (80%) target disease modification. Treatments are being assessed in secondary prevention trials with cognitively normal individuals at high risk for the development of AD. There is progress in target diversification, trial designs, outcome measures, biomarkers, and trial population definitions that promise to accelerate developing new therapies for those with or at risk for AD.