Abstract Body

There are 126 agents in clinical trials for Alzheimer’s disease (AD) as reported on clinicaltrials.gov (index date 1/4/2021). Of these 104 are putative disease modifying therapies (DMT), and 22 are directed at cognitive enhancement (13) or neuropsychiatric symptoms (9). Thirty-one of the agents are biologicals (e.g., monoclonal antibodies, vaccines) and 73 are small molecules. There at 28 agents in Phase 3, 74 in Phase 2, and 24 in Phase 1. Therapeutic targets represented by multiple agents in the pipeline include amyloid, tau, inflammation, synaptic plasticity, and metabolism/bioenergetics. Agents targeting neuropsychiatric symptoms include a repertoire of treatments for agitation; development programs also address apathy sleep, and psychosis.

The landscape of AD therapies is rapidly evolving. AD drug development has produced its first approved treatment in 17 years. Aducanumab (Aduhelmä) is an anti-amyloid monoclonal antibody directed at amyloid plaque and high molecular weight amyloid species. The FDA accepted amyloid lowering as indicative of an effect on the underlying pathophysiology of AD (e.g., a DMT). The approval of aducanumab using an accelerated approval mechanism based on amyloid lowering as demonstrated by amyloid PET provides both a new drug and a new pathway for drug approval. This will have profound consequences for AD drug development going forward. There are three monoclonal antibodies shown to reduce plaque amyloid that could be candidates for accelerated approval: lecanemab, donanemab, and gantenerumab. Previous drugs targeting amyloid and not shown to have a drug-placebo difference have not shown amyloid lowering.