Effect of TTP488 in patients with mild to moderate Alzheimer's disease

Abstract

BACKGROUND: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.