There are many promising compounds in development for Alzheimer's disease, based on substantial preclinical evidence supporting efficacy in model systems and acceptable safety data to allow chronic human exposure. Guidance for developing a clinical trial program is often held back by the absence of pharmacokinetic/pharmacodynamic (pK/pD) data to support target engagement within the central nervous system (CNS) and to aid in dose selection. For small molecules that target secretases or other key biochemical pathways in AD, studies involving CSF and plasma sampling in humans are the best way to demonstrate that a drug crosses the blood-brain barrier and engages the relevant target, and to help establish the relationship between blood levels and CNS effects. Repeated sampling through a lumbar CSF catheter over 24-36 hours, and the technique of stable metabolic labeling to measure parameters such as fractional synthesis rate of amyloid beta protein (ABeta), have helped to guide the development of gamma-secretase inhibitors developed by Pharma, but have not been available to biotechnology companies and academic laboratories. To fill this need to increase the efficacy and speed of drug development, continued CSF and plasma sampling and SILK will be established at 6 academic sites with initial proposed studies evaluating 4 candidate drugs for future ADCS Phase II/III trials.

Public Health Relevance

These methods can enable the ADCS in collaboration with Biotechnology Companies and academic laboratories to obtain critical data to guide and prioritize further clinical development of novel compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AG010483-23
Application #
8601658
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
23
Fiscal Year
2014
Total Cost
$515,012
Indirect Cost
$99,374
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Rentz, Dorene M; Dekhtyar, Maria; Sherman, Julia et al. (2016) The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials. J Prev Alzheimers Dis 3:8-12
Graff-Radford, Jonathan; Madhavan, Malini; Vemuri, Prashanthi et al. (2016) Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 12:391-8
Johnson, Keith A; Schultz, Aaron; Betensky, Rebecca A et al. (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110-9
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2016) Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. J Alzheimers Dis 50:1205-15
Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N et al. (2016) CAP--advancing the evaluation of preclinical Alzheimer disease treatments. Nat Rev Neurol 12:56-61
Raman, Mekala R; Schwarz, Christopher G; Murray, Melissa E et al. (2016) An MRI-Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease. J Neuroimaging 26:264-8
Gauthier, Serge; Feldman, Howard H; Schneider, Lon S et al. (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388:2873-2884
Le, Michelle H; Weissmiller, April M; Monte, Louise et al. (2016) Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PLoS One 11:e0147250
Tarrant, Sarah D; Bardach, Shoshana H; Bates, Kendra et al. (2016) The Effectiveness of Small-group Community-based Information Sessions on Clinical Trial Recruitment for Secondary Prevention of Alzheimer's Disease. Alzheimer Dis Assoc Disord :
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2016) Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease. Alzheimers Dement 12:527-37

Showing the most recent 10 out of 402 publications