Effect of TTP488 in patients with mild to moderate Alzheimer's disease
AffiliationTransTech Pharma, High Point, NC, USA
Department of Neurosciences, University of California, San Diego, CA, USA
Banner Sun Health Research Institute, Sun City, AZ, USA
University of Arizona, Tucson, Arizona, AZ, USA
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CitationBurstein et al. BMC Neurology 2014, 14:12 http://www.biomedcentral.com/1471-2377/14/12
Rights© 2014 Burstein et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
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AbstractBACKGROUND:TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). A previous report describes decreased decline in ADAS-cog (delta=3.1, p=0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis.METHODS:399 patients were randomized to one of two oral TTP488 doses (60mg for 6 days followed by 20mg/day
15mg for 6 days followed by 5mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL.RESULTS:On-treatment analysis demonstrated numerical differences favoring 5mg/day over placebo, with nominal significance at Month 18 (delta=2.7, p=0.03). Patients with mild AD, whether defined by MMSE or ADAS-cog, demonstrated significant differences favoring 5mg/day on ADAS-cog and trends on CDR-sb and ADCS-ADL at Month 18. TTP488 plasma concentrations of 7.6-16.8ng/mL were associated with a decreased decline in ADAS-cog over time compared to placebo. Worsening on the ADAS-cog relative to placebo was evident at 46.8-167.0ng/mL.CONCLUSIONS:Results of these analyses support further investigation of 5mg/day in future Phase 3 trials in patients with mild AD.
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