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 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/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 (60 mg for 6 days followed by 20 mg/day; 15 mg for 6 days followed by 5 mg/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 5 mg/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 5 mg/day on ADAS-cog and trends on CDR-sb and ADCS-ADL at Month 18. TTP488 plasma concentrations of 7.6-16.8 ng/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 46.8-167.0 ng/mL.
Conclusions: Results of these analyses support further investigation of 5 mg/day in future Phase 3 trials in patients with mild AD.