OBJECTIVES: To analyze the current clinical landscape of Alzheimer's disease (AD) in terms of novel versus repurposed drug molecules, comparators, classification according to CADRO (Common Alzheimer’s and Related Dementias Research Ontology), primary endpoints assessed and status of Phase II/III or III trials.

METHODS: ClinicalTrials.gov was searched for trials assessing AD up to 04 December 2023. Trials assessing non-pharmacologic intervention, diagnostic agents, and different trial methodologies were excluded. Ongoing trials and trials with completed/terminated/suspended/unknown/withdrawn status were analyzed separately.

RESULTS: Of 322 trials identified, 257 met the inclusion criteria. Out of 257 trials, 49 were ongoing, 125 completed, and 83 were terminated/suspended/unknown/withdrawn. Among 49 ongoing trials, 35 unique interventions were assessed in either Phase II/III (n=10) or III (n=39). Most of the ongoing trials (n=39) were placebo-controlled. Following the CADRO classification system, nine main targets were identified across 49 trials: β-amyloid (n=13), neurotransmitter receptors (n=15), neuroprotection/synaptic plasticity (n=8), metabolism/bioenergetics (n=5), and five other diverse targets (n=8). Further, 33 trials assessed a novel molecule while 16 assessed repurposed drugs. The key primary endpoints assessed were “cognition only” or “cognitive, functional ± behavioral” outcomes, followed by biomarkers, and safety exclusively. Out of 125 completed trials, 39 assessed USFDA-approved interventions and 28 failed to meet the primary efficacy endpoint. The other 83 trials were terminated/suspended/unknown/withdrawn due to: inability to meet the efficacy endpoint (40%), safety concerns (2%), both safety and efficacy concerns (12%), difficulty in recruiting substantial subjects (8%), unknown status (23%), and 15% trials were discontinued due to other reasons.

CONCLUSIONS: The findings reveal a diverse pipeline for AD drug development in terms of targets and treatment modalities. Nonetheless, amyloid and neurotransmitter receptor targeting continues to be prominent therapeutic strategy for AD treatment. Despite this diversity, the study highlights challenges in meeting efficacy endpoints and gaps in AD drug development, emphasizing the need for innovative solutions.