IntroductionAlzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.MethodsWe examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.ResultsDuring the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).ConclusionsThe Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.

Introduction Alzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices. Methods We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD. Results There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials. Discussion Drug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline.

Introduction Alzheimer's disease (AD) is a growing public health concern affecting millions of patients worldwide and costing billions of dollars annually. We review the pipeline of drugs and biologics in clinical trials for the treatment of AD. We use the Common Alzheimer's and Related Dementias Research Ontology (CADRO) to classify treatment targets and mechanisms of action. We review our annual pipeline reports for the past 5 years to provide longitudinal insight into clinical trials and drug development for AD. Methods We reviewed ClinicalTrials.gov as of February 27, 2020, and identified all trials of pharmacologic agents currently being developed for treatment of AD as represented on this widely used U.S. Food and Drug Administration registry. Results There are 121 agents in clinical trials for the treatment of AD. Twenty‐nine agents are in 36 Phase 3 trials, 65 agents are in 73 Phase 2 trials, and 27 agents are in 27 Phase 1 trials. Twelve agents in trials target cognitive enhancement and 12 are intended to treat neuropsychiatric and behavioral symptoms. There are 97 agents in disease modification trials. Compared to the 2019 pipeline, there is an increase in the number of disease‐modifying agents targeting pathways other than amyloid or tau. Discussion The 2020 pipeline has innovations in clinical trials and treatment targets that provide hope for greater success in AD drug development programs. Review of clinical trials over the past 5 years show that there is progressive emphasis on non‐amyloid targets, including candidate treatments for inflammation, synapse and neuronal protection, vascular factors, neurogenesis, and epigenetic interventions. There has been a marked growth in repurposed agents in the pipeline.

Introduction The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline of drugs in clinical trials for the treatment of AD. Methods We interrogated ClinicalTrials.gov, the federal registry of clinical trials to identify drugs in trials. Results There are 126 agents in 152 trials assessing new therapies for AD: 28 treatments in Phase 3 trials, 74 in Phase 2, and 24 in Phase 1. The majority of drugs in trials (82.5%) target the underlying biology of AD with the intent of disease modification; 10.3% are putative cognitive enhancing agents; and 7.1% are drugs being developed to reduce neuropsychiatric symptoms. Discussion This pipeline analysis shows that target biological processes are more diversified, biomarkers are more regularly used, and repurposed agents are being explored to determine their utility for the treatment of AD.