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Azeliragon, an oral antagonist at the Receptor for Advanced Glycation End products (RAGE) was evaluated in an 18-month Phase 2 study as treatment for patients with mild-to-moderate Alzheimer's disease (AD). Subjects with mild-to-moderate AD (MMSE14-26) treated with 5 mg azeliragon/day had a decreased decline in ADAS-cog11 at 18 months compared to placebo (Δ =3.1, p=0.008) and the mild AD subgroup (MMSE 21-26) had both decreased ADAS-cog decline compared to placebo (Δ = 4.0, p=0.02) and decreased decline in CDR-sb (Δ=1.0, p=0.02). Results from survival methodology, applied to time-to-progression analyses, demonstrate statistical support for the superiority of azeliragon over placebo and suggest that azeliragon treatment slows disease progression. Data from the mild AD (MMSE 21-26) sub-group in a previous 18-month, randomized, double-blind, placebo-controlled trial of azeliragon once daily in patients with mild-to-moderate AD (MMSE 14-26) receiving acetylcholinesterase inhibitors and/or memantine (Burstein et al. BMC Neurol 2014) were evaluated post-hoc using responder criteria for the ADAS-cog11. Responder analysis was performed using a cutpoint of a 7-point increase in ADAS-cog11 over 18 months to define progression (Vellas et al. J Nutr Health Aging 2007). Sensitivity analyses were performed examining the impact of the selected cutpoint evaluating the range of values between 1 and 20. Azeliragon (5 mg/day) demonstrates monotonically increasing differences in change in ADAS-cog11 after month 9 (Figure 1). Favorable results were seen over placebo relative to the time-to-progression (7-point increase in ADAS-cog) with a hazard ratio of 0.5 (logrank p=0.02)(Figure 2). Results were robust against the cutpoint: all cutpoints between 1 and 20 were associated with a positive result indicating a favorable effect for azeliragon. Azeliragon 5 mg/day was effective in delaying the time to cognitive deterioration (i.e. a 7-point worsening in ADAS-cog) relative to placebo in patients with mild AD. The monotonic increasing difference in ADAS-cog over placebo after month 9, combined with the previously described statistically significant less worsening of ADAS-cog and CDR-sb at 18 months in azeliragon treated patients, support the efficacy of azeliragon as a disease modifying therapy and the study of patients with mild AD in the ongoing Phase 3 STEADFAST trial. Trial registration:ClinicalTrials.gov identifier NCT00566397.