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Review
. 2018;64(s1):S3-S22.
doi: 10.3233/JAD-179901.

Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future

Jeffrey Cummings  1 , Aaron Ritter  1 , Kate Zhong  2
Affiliations
Review

Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future

Jeffrey Cummings et al. J Alzheimers Dis. 2018.

Abstract

Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

Keywords: Alzheimer’s disease; biomarkers; clinical trials; disease modifying therapies; proof-of-concept; target engagement.

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Figures

Fig.1
Fig.1
Overview of the drug development process.
Fig.2
Fig.2
Origin of compounds that are assayed through high throughput screening to produce “hits” that are then subject to medicinal chemistry refinement to produce leads and optimized leads.
Fig.3
Fig.3
Roles of biomarkers in Phase II of drug development (BACE inhibition is included as an example of one type of target engagement biomarker; each drug mechanism will have a corresponding target engagement/proof of pharmacology biomarker), CSF, cerebrospinal fluid; AD, Alzheimer’s disease; fMRI, functional magnetic resonance imaging; QEEG, quantitative electroencephalography; FDG PET, fluorodeoxyglucose positron emission tomography; NF-light, neurofilament light chain protein; ARIA, amyloid-related imaging abnormalities.
Fig.4
Fig.4
Negative (normal) and positive (abnormal; consistent with AD) amyloid PET images.
Fig.5
Fig.5
Critical data to be accrued in each stage of drug discovery and development (ADMET – absorption, distribution, metabolism, excretion, toxicity; BBB – blood brain barrier; MTD – maximum tolerated dose).
Fig.6
Fig.6
Phases of Alzheimer’s disease (AD) as defined by cognitive, functional, and biomarker observations. Trial goals for each phase are noted.
See this image and copyright information in PMC

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