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Clinical Trial
. 2014 Jan 15:14:12.
doi: 10.1186/1471-2377-14-12.

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

Aaron H Burstein  1 , Imogene Grimes, Douglas R Galasko, Paul S Aisen, Marwan Sabbagh, Adnan M M Mjalli
Affiliations
Clinical Trial

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

Aaron H Burstein et al. BMC Neurol. .

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 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.

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Figures

Figure 1
Figure 1
Estimated mean change from baseline over time on Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog 11). Increasing values represent worsening. Error bars represent one standard error. (A) ADAS-cog Observed cases all data. Treatment-placebo difference at 18 months = 3.1, p < 0.008; (B) ADAS-cog, on treatment observed cases. Treatment-placebo difference at 18 months = 2.7, p = 0.03.
Figure 2
Figure 2
Estimated mean change from baseline over time on ADAS-cog 11, CDR-sb and ADCS-ADL for patients with mild Alzheimer’s disease defined as either MMSE ≥20 (Panels A, B and C) or ADAS-cog ≤19 (Panels D, E, F) at baseline. Error bars represent one standard error. (A) ADAS-cog treatment-placebo difference at 18 months = 3.3, p = 0.024, Baseline MMSE ≥ 20; (B) CDR-sb treatment-placebo difference at 18 months = 0.72, p = 0.053, Baseline MMSE ≥ 20; (C) ADCS-ADL treatment – placebo difference at 18 months = 2.2, p = 0. 3, Baseline MMSE ≥ 20 (D) ADAS-cog treatment-placebo difference at 18 months = 5.9, p < 0.008, Baseline ADAS-cog ≤ 19; (E) CDR-sb treatment-placebo difference at 18 months = 1, p = 0.08, Baseline ADAS-cog ≤ 19; (F) ADCS-ADL treatment-placebo difference at 18 months = 4.92, p = 0.07, Baseline ADAS-cog ≤ 19.
Figure 3
Figure 3
TTP488 plasma concentration over time. On-treatment data where on-treatment is defined as plasma concentrations measured within 45 days of last administered dose. Data presented as mean values with 95% confidence boundary. For the 20 mg/day group data presented through Month 15 after which there were too few observations.
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