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.
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.
|Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7|
|Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol 71:1379-85|
|Rafii, Michael S; Taylor, Curtis S; Kim, Hyun T et al. (2014) Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease. Am J Alzheimers Dis Other Demen 29:159-65|
|Whitehouse, Peter J (2014) The end of Alzheimer's disease--from biochemical pharmacology to ecopsychosociology: a personal perspective. Biochem Pharmacol 88:677-81|
|Burstein, Aaron H; Grimes, Imogene; Galasko, Douglas R et al. (2014) Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol 14:12|
|Donohue, Michael C; Jacqmin-Gadda, Hélène; Le Goff, Mélanie et al. (2014) Estimating long-term multivariate progression from short-term data. Alzheimers Dement 10:S400-10|
|Samieri, Cécilia; Proust-Lima, Cécile; M Glymour, Maria et al. (2014) Subjective cognitive concerns, episodic memory, and the APOE ?4 allele. Alzheimers Dement 10:752-759.e1|
|Galasko, Douglas; Bell, Joanne; Mancuso, Jessica Y et al. (2014) Clinical trial of an inhibitor of RAGE-A? interactions in Alzheimer disease. Neurology 82:1536-42|
|Sperling, Reisa A; Rentz, Dorene M; Johnson, Keith A et al. (2014) The A4 study: stopping AD before symptoms begin? Sci Transl Med 6:228fs13|
|Papay, Kimberly; Xie, Sharon X; Stern, Matthew et al. (2014) Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology 83:826-33|
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